Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds

ABSTRACT

The present invention relates to novel cinnamide compounds that are useful for treating inflammatory and immune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.

TECHNICAL FIELD

The present invention relates to compounds that are useful for treatinginflammatory and immune diseases, to pharmaceutical compositionscomprising these compounds, and to methods of inhibiting inflammation orsuppressing immune response in a mammal.

BACKGROUND OF THE INVENTION

Inflammation results from a cascade of events that includes vasodilationaccompanied by increased vascular permeability and exudation of fluidand plasma proteins. This disruption of vascular integrity precedes orcoincides with an infiltration of inflammatory cells. Inflammatorymediators generated at the site of the initial lesion serve to recruitinflammatory cells to the site of injury. These mediators (chemokinessuch as IL-8, MCP1, MIP-1, and RANTES, complement fragments and lipidmediators) have chemotactic activity for leukocytes and attract theinflammatory cells to the inflamed lesion. These chemotactic mediatorswhich cause circulating leukocytes to localize at the site ofinflammation require the cells to cross the vascular endothelium at aprecise location. This leukocyte recruitment is accomplished by aprocess called cell adhesion.

Cell adhesion occurs through a coordinately regulated series of stepsthat allow the leukocytes to first adhere to a specific region of thevascular endothelium and then cross the endothelial barrier to migrateto the inflamed tissue (Springer, T. A., 1994, “Traffic Signals forLymphocyte Recirculation and Leukocyte Emigration: The MultistepParadigm, Cell ” Cell ( 1994 ) 76:301-314; Lawrence, M. B., andSpringer, T. A., 1991, “Leukocytes' Roll on a Selectin at PhysiologicFlow Rates: Distinction from and Prerequisite for Adhesion ThroughIntegrins, Cell. ” Cell ( 1991 ) 65:859-873; Von Adrian, U., Chambers,J. D., McEnvoy, L. M., Bargatze, R. F., Arfos, K. E. and Butcher, E. C.,1991, “Two-Step Model of Leukocyte-Endothelial Cell Interactions inInflammation, Proc. Natl. Acad. Sci. USA ” Proc. Natl. Acad. Sci. USA (1991 ) 88: 7538-7542; and Ley, K., Gaehtgens, P., Fennie, C., Singer, M.S., Lasky, L. H. and Rosen, S. D., 1991, “Lectin-Like Cell AdhesionMolecule 1 Mediates Rolling in Mesenteric Venules in vivo, Blood InVivo,” Blood ( 1991 ) 77: 2553-2555). These steps are mediated byfamilies of adhesion molecules such as integrins, Ig supergene familymembers, and selectins which are expressed on the surface of thecirculating leukocytes and on the vascular endothelial cells. The firststep consists of leukocytes rolling along the vascular endothelial celllining in the region of inflammation. The rolling step is mediated by aninteraction between a leukocyte surface oligosaccharide, such asSialylated Lewis-X antigen (Slex), and a selectin molecule expressed onthe surface of the endothelial cell in the region of inflammation. Theselectin molecule is not normally expressed on the surface ofendothelial cells but rather is induced by the action of inflammatorymediators such as TNF-α and interleukin-1. Rolling decreases thevelocity of the circulating leukocytes in the region of inflammation andallos the cells to more firmly adhere to the endothelial cell. The firmadhesion is accomplished by the interaction of integrin molecules thatare present on the surface of the rolling leukocytes and theircounter-receptors (the Ig superfamily molecules) on the surface of theendothelial cell. The Ig superfamily molecules or CAMs (Cell AdhesionMolecules) are either not expressed or are expressed at low levels onnormal vascular endothelial cells. The CAM's CAMs, like the selectins,are induced by the action of inflammatory mediators like TNF-alpha andIL-1. The final event in the adhesion process is the extravasation ofleukocytes through the endothelial cell barrier and their migrationalong a chemotactic gradient to the site of inflammation. Thistransmigration is mediated by the conversion of the leukocyte integrinfrom a low avidity state to a high avidity state. The adhesion processrelies on the induced expression of selectins and CAM's CAMs on thesurface of vascular endothelial cells to mediate the rolling and firmadhesion of leukocytes to the vascular endothelium.

The interaction of the intercellular adhesion molecule ICAM-1 (cd54) onendothelial cells with the integrin LFA-1 on leukocytes plays animportant role in endothelial-leukocyte contact. Leukocytes bearinghigh-affinity LFA-1 adhere to endothelial cells through interaction withICAM-1, initiating the process of extravasation from the vasculatureinto the surrounding tissues. Thus, an agent which blocks theICAM-1/LFA-1 interaction suppresses these early steps in theinflammatory response. Consistent with this background, ICAM-1 knockoutmice have numerous abnormalities in their inflammatory responses.

The present invention application discloses compounds which bind to theinteraction-domain (1-domain) (I-domain) of LFA-1, thus interruptingendothelial cell-leukocyte adhesion by blocking the interaction of LFA-1with ICAM-1, ICAM-3, and other adhesion molecules. These compounds areuseful for the treatment of prophylaxis of diseases in which leukocytetrafficking plays a role, notably acute and chronic inflammatorydiseases, autoimmune diseases, tumor metastasis, allograft rejection,and reperfusion injury. The compounds of this invention are diarylsulfides, which are substituted with a cinnamide moiety. The cinnamidefunctionality may be placed either ortho- or para- to the linking sulfuratom, although para-substitution is preferable. Appropriate substitutionof both aromatic rings is tolerated, and can be used to modulate avariety of biochemical, physicochemical and pharmacokinetic properties.In particular the amide moiety is readily modified; a variety ofsecondary and tertiary amides are active, and alternatively aheterocyclic ring may be attached at this position. Modifications ofthis amide functionality are particularly useful in modulatingphysico-chemical and pharmacokinetic properties.

SUMMARY OF THE INVENTION

In one embodiment of the present invention are disclosed compoundsrepresented by structural Formula I, below,

or a pharmaceutically-acceptable salt or pharmaceutically-acceptableprodrug thereof of a compound of Formula I,

-   -   wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from        -   a. hydrogen,        -   b. halogen,        -   c. alkyl,        -   d. haloalkyl,        -   e. alkoxy,        -   f. cyano,        -   g. nitro,        -   h. carboxaldehyde, and    -   with the proviso that at leastwhere one or both of R₁ orand R₃,        which may be the same or different, is a “cis-cinnamide” or a        “trans-cinnamide”, defined as    -   whereinwhere R₈ and R₉ are each independently selected from        -   -   a. hydrogen, and            -   b. alkyl,            -   c. carboxy alkyl,            -   d. alkylaminocarbonyl alkyl monoalkylaminocarbonylalkyl,                and            -   e. dialkylaminocarbonyl alkyl,    -   and R₁₀ and R₁₁ are each independently selected from        -   -   a. hydrogen,            -   b. alkyl,            -   c. cycloalkyl,            -   d. alkoxycarbonylalkyl,            -   e. hydroxyalkyl, and            -   f. heterocyclylalkyl,

        -   or where NR₁₀R₁₁ is R₁₀ and R ₁₁ are taken together with the            N to form an unsubstituted heterocyclyl group, or a            substituted heterocyclyl group, where the substituted            heterocyclyl group is substituted by one or more than one            substituent, where the substituents are each independently            selected from            -   1) alkyl,            -   2) alkoxy,            -   3) alkoxyalkyl,            -   4) cycloalkyl,            -   5) aryl,            -   6) heterocyclyl,            -   7) heterocyclylcarbonyl,            -   8) heterocyclylalkylaminocarbonyl,            -   9) hydroxy,            -   10) hydroxyalkyl,            -   11) hydroxyalkoxyalkyl,            -   12) carboxy,            -   13) carboxycarbonyl,            -   14) carboxaldehyde,            -   15) alkoxycarbonyl,            -   16) arylalkoxycarbonyl,            -   17) aminoalkanoyl,            -   18) carboxamido,            -   19) alkoxycarbonylalkyl,            -   20) carboxamidoalkyl,            -   21) alkanoyl,            -   22) hydroxyalkanoyl,            -   23) alkanoyloxy,            -   24) alkanoylamino,            -   25) alkanoyloxyalkyl, and            -   26) alkylsulfonyl,                R₁ , if it is not “cis-cinnamide” or “trans-cinnamide”,                as defined above, R ₃ , if it is not “cis-cinnamide” or                “trans-cinnamide”, as defined above, R ₂ , R ₄ , and R ₅                , are each independently selected from    -   a. hydrogen,    -   b. halogen,    -   c. alkyl,    -   d. haloalkyl,    -   e. alkoxy,    -   f. cyano,    -   g. nitro, and    -   h. carboxaldehyde,        and wherein Ar is an unsubstituted aryl group, an unsubstituted        heteroaryl group, a substituted aryl group, or a substituted        heteroaryl group, where the substituted aryl group and the        substituted heteroaryl group are substituted by one or more than        one substituent, where substitutionsthe substituents are each        independently selected from    -   a. hydrogen,    -   b.a. halogen,    -   c.b. alkyl,    -   d.c. aryl,    -   e.d. haloalkyl,    -   f.e. hydroxy,    -   g.f. alkoxy,    -   h.g. alkoxycarbonyl,    -   i.h. alkoxyalkoxy,    -   j.i. hydroxyalkyl,    -   k.j. aminoalkyl,    -   l.k. alkyl(alkoxycarbonylalkyl)aminoalkyl,    -   m.l. unsubstituted heterocyclylalkyl,    -   n.m. substituted heterocyclylalkyl,    -   o.n. carboxaldehyde,    -   p.o. carboxaldehyde hydrazone,    -   q.p. carboxamide,    -   r.q. alkoxycarbonyl alkyl,    -   s.r. hydroxycarbonylalkyl (carboxyalkyl),    -   t.s. cyano,    -   u.t. amino,    -   v.u. heterocyclylalkylamino, and    -   w.v. “trans-cinnamide”.,        subject to the proviso that when R ₃ is a “cis-cinnamide” or a        “trans-cinnamide,” as defined above, one or more than one of the        following conditions is fulfilled:    -   (A) Ar is an unsubstituted heteroaryl group, a substituted        heteroaryl group, or a substituted aryl group;    -   (B) one or more than one of R ₁ , R ₂ , R ₄ , and R ₅ , as        defined above, are other than hydrogen; and    -   (C) R ₁₀ and R ₁₁ are taken together with N to form a        substituted or unsubstituted heterocyclyl group, as defined        above.

In another embodiment of the invention are disclosed compoundsrepresented by structural Formula I, above, when prepared by syntheticprocesses or by metabolic processes. Preparation of the compounds of thepresent invention by metabolic processes include those occurring in thehuman or animal body (in vivo) or by processes occurring in vitro.

In another embodiment of the invention are disclosed methods oftreatment or prophylaxis in which the inhibition of inflammation orsuppression of immune response is desired, comprising administering aneffective amount of a compound having Formula I.

In yet another embodiment of the invention are disclosed pharmaceuticalcompositions containing compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

The term “alkanoyl” as used herein refers to an alkyl group attached tothe parent molecular group through a carbonyl group.

The term “alkanoylamino” as used herein refers to an alkanoyl groupattached to the parent molecular group though an amino group.

The term “alkanoyloxy” as used herein refers to an alkanoyl groupattached to the parent molecular group through an oxygen radical.

The term “alkanoyloxyalkyl” as used herein refers to an alkanoyloxygroup attached to the parent molecular group through an alkyl group.

The term “alkoxy” as used herein refers to an alkyl group attached tothe parent molecular group through an oxygen atom.

The term “alkoxyalkoxy” as used herein refers to an alkoxy groupattached to the parent molecular group through an alkoxy group.

The term “alkoxyalkyl” as used herein refers to an alkoxy group attachedto the parent molecular group through an alkyl group.

The term “alkoxycarbonyl” as used herein refers to an alkoxy groupattached to the parent molecular group through a carbonyl group.

The term “alkoxycarbonylalkyl” as used herein refers to analkoxycarbonyl group attached to the parent molecular group through analkyl group.

The term “alkyl” as used herein refers to a saturated straight orbranched chain radical group of 1-10 carbon atoms derived from an alkaneby the removal of one hydrogen atom.

The term “alkyl(alkoxycarbonylalkyl)amino” as used herein refers to anamino group substituted with one alkyl group and one alkoxycarbonylalkylgroup.

The term “alkyl(alkoxycarbonylalkyl)aminoalkyl” as used herein refers toan alkyl(alkoxycarbonylalkyl)amino group attached to the parentmolecular group through an alkyl group.

The term “alkylene” as used herein refers to a divalent group of 1-10carbon atoms derived from a straight or branched chain alkane by theremoval of two hydrogen atoms.

The term “alkylsulfonyl” as used herein refers to an alkyl radicalattached to the parent molecular group through an —SO₂— group.

The term “amino” as used herein refers to a radical of the form—NR₁₈R₁₉, or to to a radical of the form —NR₁₈—, where R₁₈ and R₁₉ areindependently selected from hydrogen, alkyl or cycloalkyl.

The term “aminoalkanoyl” as used herein refers to to an amino groupattached to the parent molecular group through an alkanoyl group.

The term “aminoalkyl” as used herein refers to an amino group attachedto the parent molecular group through an alkyl group.

The term “aryl” as used herein refers to a mono- or bicyclic carbocyclicring system having one or two aromatic rings. The aryl group can also befused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring.The aryl groups of this invention can be optionally substituted withalkyl, halogen, hydroxy, or alkoxy substituents.

The term “arylalkoxy” as used herein refers to an aryl group attached tothe parent molecular group through an alkoxy group.

The term “arylalkoxycarbonyl” as used herein refers to an arylalkoxygroup attached to the parent molecular group through a carbonyl group.

The term “carboxaldehyde” as used herein refers to the radical —CHO.

The term “carboxaldehyde hydrazone” as used herein refers to the radical—CH═N—NR₂₀R₂₁, where R₂₀ and R₂₁ are independently selected fromhydrogen, alkyl or cycloalkyl.

The terms “carboxamide” or “carboxamido” as used herein refer to anamino group attached to the parent molecular group through a carbonylgroup.

The term “carboxamidoalkyl” as used herein refers to a carboxamido groupattached to the parent molecular group through an alkyl group.

The term “carboxy” as used herein refers to the radical —COOH.

The term “carboxycarbonyl” as used herein refers to a carboxy groupattached to the parent molecular group through a carbonyl group.

The term “cyano” as used herein refers to the radical —CN.

The term “cycloalkyl” as used herein refers to a monovalent saturatedcyclic or bicyclic hydrocarbon group of 3-12 carbons derived from acycloalkane by the removal of a single hydrogen atom. Cycloalkyl groupsmay be optionally substituted with alkyl, alkoxy, halo, or hydroxysubstituents.

The terms “halo” or “halogen” as used herein refers to F, Cl, Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms.

The terms “heterocycle” or “heterocyclyl” represent a 4-, 5-, 6- or7-membered ring containing one, two or three heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur. The4- and 5-membered rings have zero to two double bonds and the 6- and7-membered rings have zero to three double bonds. The term “heterocycle”or “heterocyclic” as used herein additionally refers to bicyclic,tricyclic and tetracyclic groups in which any of the above heterocyclicrings is fused to one or two rings independently selected from an arylring, a cyclohexane ring, a cyclohexane ring, a cyclopentane ring, acyclopenetene ring or another monocyclic heterocyclic ring. Heterocyclesinclude acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl,homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl,isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,morpholinyl, oxadizolyl, oxazolidinyl, oxazolyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl,pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl,tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,thiadiazolyl, thiazolidinyl, thiazolyl, thienyl,thiomorpholinyl,triazolyl, and the like.

Heterocyclics also include bridged bicyclic groups where a monocyclicheterocyclic group is bridged by an alkylene group such as

and the like.

Heterocyclics also include compounds of the formula

where X* and Z* are independently selected from —CH₂—, —CH₂NH—, —CH₂O—,—NH— and —O—, with the proviso that at least one of X* and Z* is not—CH₂—, and Y* is selected from —C(O)— and —(C(R″)₂)_(v)—, where R″ ishydrogen or alkyl of one to four carbons, and v is 1-3. Theseheterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl,1,3-benzimidazol-2-one and the like. The heterocycle groups of thisinvention can be optionally substituted with alkyl, halogen, hydroxy oralkoxy substituents.

The term “heterocyclylalkyl” as used herein refers to an heterocyclicgroup attached to the parent molecular group through an alkyl group.

The term “heterocyclylalkylamino” as used herein refers to anheterocyclylalkyl group attached to the parent molecular group throughan amino group.

The term “heterocyclylalkylaminocarbonyl” as used herein refers to aheterocyclylalkylamino group attached to the parent molecular groupthrough a carbonyl group.

The term “heterocyclylcarbonyl” as used herein refers to a heterocyclylgroup attached to the parent molecular group through a carbonyl group.

The term “hydroxyalkanoyl” as used herein refers to an hydroxy radicalattached to the parent molecular group through an alkanoyl group.

The term “hydroxyalkoxy” as used herein refers to an hydroxy radicalattached to the parent molecular group through an alkoxy group.

The term “hydroxyalkoxyalkyl” as used herein refers to an hydroxyalkoxygroup attached to the parent molecular group through an alkyl group.

The term “hydroxyalkyl” as used herein refers to an hydroxy radicalattached to the parent molecular group through an alkyl group.

The term “perfluoroalkyl” as used herein refers to an alkyl group inwhich all of the hydrogen atoms have been replaced by fluoride atoms.

The term “phenyl” as used herein refers to a monocyclic carbocyclic ringsystem having one aromatic ring. The phenyl group can also be fused to acyclohexane or cyclopentane ring. The phenyl groups of this inventioncan be optionally substituted with alkyl, halogen, hydroxy or alkoxysubstituents.

The term “pharmaceutically-acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals with withoutundue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention.

The term “prodrug”, as used herein, represents compounds which arerapidly transformed in vivo to the parent compound of the above formula,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “thioalkoxy” as used herein refers to an alkyl group attachedto the parent molecular group through a sulfur atom.

Compounds of the present invention can exist as stereoisomers whereinasymmetric or chiral centers are present. These compounds are designatedby the symbols “R” or “S,” depending on the configuration ofsubstituents around the chiral carbon atom. The present inventioncontemplates various stereoisomers and mixtures thereof. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers are designated (±). Individual stereoisomers of compoundsof the present invention can be prepared synthetically from commerciallyavailable starting materials which contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution well-knownto those of ordinary skill in the art. These methods of resolution areexemplified by (1) attachment of a mixture of enantiomers to a chiralauxiliary, separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns.

Geometric isomers can also exist in the compounds of the presentinvention. The present invention contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the Z^(j) or Econfiguration wherein the term “Z” represents substituents on the sameside of the carbon-carbon double bond and the term “E” representssubstituents on opposite sides of the carbon-carbon double bond. Thearrangement of substituents around a carbocyclic ring are designated ascis or trans wherein the term “cis” represents substituents on the sameside of the plane of the ring and the term “trans” representssubstituents on opposite sides of the plane of the ring. Mixtures ofcompounds wherein the substituents are disposed on both the same andopposite sides of plane of the ring are designated cis/trans.

As is apparent from the foregoing descriptions, the compounds of FormulaI are useful in a variety of forms, i.e., with various substitutions asidentified. Examples of particularly desirable compounds are quitediverse, and many are mentioned herein. Included are compounds in whichR₁ is a “cis-cinnamide” or a “trans-cinnamide”, and R₃ is hydrogen; orwhere R₃ is a “cis-cinnamide” or a “trans-cinnamide”, and R₁ ishydrogen, or R₁, R₂, and R₄ are each independently hydrogen or alkyl,and R₅ is halogen, haloalkyl or nitro. Further preferred compoundsinclude those as above wherein R₁₀ and R₁₁ are each in dependentlyhydrogen, alkyl, cycloalkyl, alkoxycarbonylaalkyl, hydroxyalkyl, orheterocyclylalkyl, or where NR₁₀R₁₁, is heterocyclyl or substitutedheterocyclyl, and where Ar is aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl.

Compounds of the present invention include, but are not limited to:

-   (2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-E-((3-(1-imidazolyl)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)amino)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 3 -(    2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-(Hydroxymethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethoxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((3-(hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((2-(hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((4-(hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((4-(1-benzimidazol-2-only)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   ( 2-Bromophenyl) 2-chloro-4 -(E-(( 4 -(    2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoquinolinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Methyliphenyl)[2-trifluoromethyl-4-(E-((2-(-morpholinyl)ethylamino)carbonyl)ethenyl)phenyl]sulfide;-   ( 2-Methylphenyl)[2-trifluoromethyl-4 -(E-(( 2 -(    1-morpholinyl)ethylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   ( 2-Methylphenyl)[2-trifluoromethyl-4 -(E-(( 3 -(    2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   ( 2,4-Dichlorophenyl) 2-nitro-4 -(E-(( 3 -(    2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (4-Methylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-tert-butoxycarbonylmethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Hydroxymethyl)phenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl))2-propenyl)phenyl]sulfide;-   (2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-(E-((1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Formylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;-   (2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide,    N,N-dimethyl hydrazone;-   (2-((3-(1-Morpholinyl)propyl)-1-amino)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   ( 2,4-Dichlorophenyl)[2-bromo-4 -(E-(( 3 -(    2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;-   (2,4-Dichlorophenyl)[2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;    and-   (2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide.    Pharmaceutical Compositions and Methods of Treatment

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more pharmaceutically-acceptable carriers.The pharmaceuticalcompositions may be specially formulated for oral administration insolid or liquid form, for parenteral injection, or for rectaladministration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.The term “parenteral” administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically-acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativepreservatives, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and antifungal agents, for example,paraben, chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like, . Prolonged absorption of the injectable pharmaceuticalform may be brought about by the inclusion of agents which delayabsorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly (orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically-acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (I i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs. In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifing and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers sucha scocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically-acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

The compounds of the present invention may be used in the form ofpharmaceutically-acceptable salts derived from inorganic or organicacids. By “pharmaceutically-acceptable salt” is meant those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio.Pharmaceutically-acceptable salts are well-known in the art. Forexample, S. M. Berge, et al. Describe , describepharmaceutically-acceptable salts in detail in J. PharmaceuticalSciences , J. Pharmaceutical Sciences ( 1977 ) 1977, 66; 1 et seq. Thesalts may be prepared in situ in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable acid. Representative acid additionsalts include, but are not limited to acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water Water-soluble, oroil-soluble, or dispersible products are thereby obtained. Examples ofacids which may be employed to form pharmaceutically acceptable acidaddition salts include such inorganic acids as hydrochloric acid,hydrobromic acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ in situ during the finalisolation and purification of compounds of this invention by reacting acarboxylic acid-containing moiety with a suitable base such as thehydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically-acceptable basic addition saltsinclude, but are not limited to, cations based on alkali metals oralkaline earth metals such as lithium, sodium, potassium, calcium,magnesium and , aluminum salts and the like and nontoxic quaternaryammonia and amine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically-acceptablecarrier and any needed preservatives, buffers, or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

Generally dosage levels of about 0.1 to about 50 mg, more preferably ofabout 5 to about 20 mg of active compound per kilogram of body weightper day are administered orally or intravenously to a mammalian patient.If desired, the effective daily dose may be divided into multiple dosesfor purposes of administration, e.g. two to four separate doses per day.

Preparation of Compounds of this Invention

The compounds and processes of the present invention may be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention can beprepared.

Scheme 1 describes the synthesis of a typical cinnamide-substituteddiaryl sulfide 4 through an aldehyde intermediate 2. Aldehyde 2 isprepared by reaction of a thiophenol (for example2,4-dichlorothiophenol, 2-bromothiophenol, or the like) withhalo-substituted benzaldehyde derivative 1 (e.g. 2-chlorobenzaldehyde,3-chloro,4-fluorobenzaldehyde, or the like) in the presence of base(e.g. sodium carbonate, triethylamine, or the like) and a polar solvent(e.g. dimethylformamide, dimethylsulfoxide, or the like). The aldehydegroup is homologated to the corresponding cinnamic acid 3, using anacetate equivalent (for example, malonic acid,triethoxyphosphonoacetate, or the like) in the presence of anappropriate base and solvent. In some cases, it may be necessary tohydrolyze an intermediate ester (for example using sodium hydroxide inalcohol). The acid group is activated (for example using thionylchloride, or dicyclohexylcarbodiimide and N-hydroxysuccinimide, or thelike) and reacted with a primary or secondary amine (for example,6-aminohexanol, pyrrolidone-3-propylamine, or the like) to provide thedesired analog 4. In one variant, a haloacetophenone can replacebenzaldehyde 2; the resultant cinnamides 4 are substituted with a methylgroup at the 3-position.

Alternatively, the order of these coupling steps may be reversed (Scheme2). A substituted halocinnamic acid 5 (e.g. 3-chloro,2-nitrocinnamicacid or the like) may be coupled with a primary or secondary amine (e.g.N-acetylpiperazine or the like) as described above to give thecorresponding amide 6. The halo-group can then be displaced with asubstituted thiophenol in the presence of base to provide the product 7.

A number of the compounds described herein may be prepared fromintermediate benzylic alcohols like 8 (Scheme 3) Activation of thealcohol moiety (for example, using phosphorus tribromide ormethanesulfonyl chloride and lithium halide in dimethylformamide) anddisplacement with a primary or secondary amine (e.g. morpholine,N-formylpiperazine or the like) provides analogs with structures relatedto 9. Alternatively the alcohol may be oxidized (for example using TPAPor PCC or the like) to give aldehyde 10.

Cinnamides like 13 may be prepared from halo-substituted derivatives 11by palladium-mediated coupling [e.g. using tetrakis (o-tolyl phosphine)palladium (0), Pd₂ (dba)₃, or the like] with acrylamide derivatives 12(Scheme 4). In similar manner, anilino-cinnamides like 16 can beprepared by palladium-mediated coupling of amines 15 withhalo-cinnamides 14.

In some cases, functional groups on the aromatic rings can be modifiedto produce new analogs (Scheme 5). For example, a nitro group incompounds like 17 may be reduced (for example, with tin(II) chloride, orby catalytic hydrogenation, or the like) to the corresponding amine 18.This amine may then itself be converted to a halogen, for example bydiazotization using nitrous acid or t-butyl nitrite in the presence of ametal halide salt like cupric bromide, providing analog 19.

It is also possible to assemble cinnamide-substituted diaryl sulfides ina “reverse” sense (Scheme 6). Thus, for example, compound 20, preparedas described in Scheme 1, may be deprotected by treatment with base(e.g. potassium t-butoxide or the like) to provide thiolate anion 21,which may be reacted with an activated haloarene (e.g.2,3-dichlorobenzaldehyde, 3-chloro,4-fluorobenzaldehyde or the like) toprovide the corresponding product 22.

The compounds and processes of the present invention will be betterunderstood in connection with the following examples which are intendedas an illustration of and not a limitation upon the scope of theinvention.

EXAMPLE 1(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfideEXAMPLE 1A 2-[(2,4-Dichlorophenyl)thio]benzaldehyde

To a stirred solution of 2,4-dichlorothiophenol (2.0 g, 11.2 mmol) in 25mL of anhydrous DMF was added potassium carbonate (3.09 g, 22.4 mmol),followed by 2-chlorobenzaldehyde (1.26 mL, 11.3 mmol). The mixture wasthen heated under nitrogen atmosphere at 70° C. for 5 hours. Thereaction mixture was then allowed to cool to room temperature andpartitioned between ether and water. The aqueous layer was extractedwith ether once and the combined organic layer was washed with water andbrine, dried over sodium sulfate and condensed in vacuo. The crudeproduct was purified via silica gel flash chromatography, eluting with5-10% ether/hexanes, to give 2.62 g (9.25 mmol, 83%) of the desiredaldehyde as a colorless oil, which solidified slowly upon standing atroom temperature.

EXAMPLE 1B trans-2-[(2,4-Dichlorophenyl)thio]cinnamic acid

A mixture of the aldehyde (1.50 g, 5.3 mmol) from Example 1A, malonicacid (1.21 g, 11.6 mmol), piperidine (78.6 μL, 0.80 mmol) in 8.0 mL ofanhydrous pyridine was heated at 110° C. for 2 hours. Gas evolutionceased during this period. Pyridine was then removed under vacuum. Waterand 3N aq. HCl were then added with stirring. The desired cinnamic acidwas then collected through filtration, washed with cold water and driedin a vacuum oven overnight to give 1.56 g (4.8 mmol, 91%) of whitesolid.

EXAMPLE 1C(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide

A suspension of the acid (284 mg, 0.87 mmol) from Example 1B in 5 mL ofmethylene chloride was stirred with (COCl)₂ (84 μL, 0.97 mmol), and onedrop of DMF under nitrogen atmosphere for 90 minutes. The solvent wasthen removed under vacuum. The residue (COCl)₂ was removed with benzene(2×) in vacuo. To a separate flask, previously filled with6-amino-1-hexanol (12 mg, 0.10 mmol), Hunig's base (22.8 μL, 0.13 mmol)and DMAP (1.1 mg, 0.008 mmol) in 2.0 mL of CH₂Cl₂, the acid chloride (30mg, 0.087 mmol) in 1.0 mL of CH₂Cl₂ was then dropped in slowly. After 30minutes, the reaction mixture was poured into 3N HCl and extracted withethyl aceetate (EtOAc). The organic layer was washed with brine, driedwith Na₂SO₄, condensed under reduced pressure. The crude product waspurified by preparative TLC to give 21.0 mg (90%) of the title compoundas a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ 1.31-1.48 (m, 4H),1.48-1.70 (m, 4H), 3.37 (q, J=6.7 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 5.63(br s, 1H), 6.36 (d, J=15.9 Hz, 1H), 6.71 (d, J=9.3 Hz, 1H), 7.95 (dd,J=2.4, 8.7 Hz, 1H), 7.31-7.49 (m, 4H), 7.65 (dd, J=2.1, 7.5 Hz, 1H),7.99 (d, J=15.9 Hz, 1H). MS (DSI/NH₃) (M+NH₄)⁺ at m/z 441, 443, 445.

EXAMPLE 2(2,4-Dichlorophenyl)[2-(E-((3-(1-imidazolyl)propylamino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example1C substituting 6-amino-1-hexanol with 1-(3-aminopropyl)imidazole. Whitepowder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.88 (p, J=7.7 Hz, 2H), 3.11 (q,J=7.7 Hz, 2H), 3.97 (t, J=7.7 Hz, 2H), 6.63 (d, J=15.9 Hz, 1H), 6.70 (d,J=8.7 Hz, 1H), 6.89 (d, J=0.9 Hz, 1H), 7.17 (d, J=0.9 Hz, 1H), 7.33 (dd,J=2.7, 8.7 Hz, 1H), 7.46-7.65 (m, 4H), 7.72 (d, J=2.7 Hz, 1H), 7.78 (d,J=15.9 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 8.24 (t, J=5.9 Hz, 1H). MS(DCI/NH₃) (M+H)⁺ at m/z 448, 450, 452. Analysis calculated forC₂₁H₁₉N₃O₁Cl₃S₁.0.87H₂O: C, 56.30; H, 4.67; N, 9.38. Found: C, 56.30; H,4.56; N, 9.27.

EXAMPLE 3(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with ethanolamine.Colorless oil; ¹H NMR (CDCl₃, 300 MHz) δ 3.57 (q, J=7.65 Hz, 2H), 3.71(q, J=7.65 Hz, 2H), 6.06 (br s, 1H), 6.40 (d, J=15.3 Hz, 1H), 6.96 (d,J=8.7 Hz, 1H), 7.22-7.30 (m, 4H), 7.49-7.60 (m, 1H), 7.55 (d, J=15.3 Hz,1H). MS (APCI) (M+H)⁺ at m/z 402, 404, 406, 408. Analysis calculated forC₁₇H₁₄N₁O₂Cl₃S₁.0.25H₂O: C, 50.14; H, 3.59; N, 3.44. Found: C, 50.16; H,3.62; N, 3.29.

EXAMPLE 4(2,4-Dichlorophenyl)[2-chloro-4-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde. Colorless oil; ¹H NMR (CDCl₃, 300 MHz) δ1.42 (m, 4H), 1.58 (m, 4H), 3.40 (q, J=6.7 Hz, 2H), 3.65 (br m, 2H),5.60 (br t, 1H), 6.35 (d, J=15.3 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H),7.22-7.30 (m, 4H), 7.49-7.60 (m, 1H), 7.55 (d, J=15.3 Hz, 1H). MS (APCI)(M+H)⁺ at m/z 458, 460, 462, 464. Analysis calculated forC₂₁H₂₂N₁O₂Cl₃S₁.0.27H₂O: C, 54.39; H, 4.90; N, 3.02. Found: C, 54.40; H,4.85; N, 2.71.

EXAMPLE 5(2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)amino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol withdiethanolamine. Colorless oil; ¹H NMR (CDCl₃, 300 MHz) δ 2.99 (br s,2H), 3.67 (br m, 4H), 3.88 (t, J=5.1 Hz, 2H), 3.94 (t, J=5.1 Hz, 2H),6.94 (d, J=1.53 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.21-7.32 (m, 3H),7.50-7.54 (m, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.58 (d, J=15.3 Hz, 1H). MS(APCI) (M+H)⁺ at m/z 446, 448, 450, 452. Analysis calculated forC₁₉H₁₈N₁O₃Cl₃S₁.1.09H₂O: C, 48.93; H, 4.36; N, 3.00. Found: C, 48.88; H,4.00; N, 3.01.

EXAMPLE 6(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide(2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 3 -(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with1-(3-aminopropyl)-2-pyrrolidinone. Colorless oil; ¹H NMR (CDCl₃, 300MHz) δ 1.74 (qu, J=6.0 Hz, 2H), 2.09 (qu, J=7.5 Hz, 2H), 2.45 (t, J=8.25Hz, 2H), 3.33 (q, J=6.0 Hz, 2H), 3.42 (q, J=8.25 Hz, 4H), 6.46 (d,J=15.6 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 7.14-7.23 (m, 2H), 7.30 (dd,J=2.4, 8.7 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H). 7.51 (d, J=15.6 Hz, 1H),7.60 (d, J=2.1 Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 483, 485, 487, 489.Analysis calculated for C₂₂H₂₁N₂O₂Cl₃S₁.0.57H₂O: C, 53.48; H, 4.52; N,5.67. Found: C, 53.49; H, 4.60; N, 5.65.

EXAMPLE 7(2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with morpholine.White solid; ¹H NMR (CDCl₃, 300 MHz) δ 3.59-3.80 (m, 8H), 6.83 (d,J=15.6 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.16-7.32 (m, 3H), 7.49-753 (m,1H), 7.59 (d, J=2.4 Hz, 1H), 7.59 (d, J=15.6 Hz, 1H). MS (DCI/NH₃)(M+H)⁺ at m/z 428, 430, 432, 434. Analysis calculated forC₁₉H₁₆N₁O₂Cl₃S₁.0.46H₂O: C, 52.22; H, 3.90; N, 3.20. Found: C, 52.20; H,3.76; N, 3.12.

EXAMPLE 8(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with1-methylpiperazine. Colorless oil; ¹H NMR (CDCl₃, 300 MHz) δ 2.37 (s,3H), 2.51 (br m, 4H), 3.64-3.87 (br m, 4H), 6.85 (d, J=15.6 Hz, 1H),6.98 (d, J=8.7 Hz, 1H), 7.19-7.25 (m, 2H), 7.27 (dd, J=2.1, 8.7 Hz, 1H),7.52 (t, J=0.9 Hz, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H).MS (DCI/NH₃) (M+H)⁺ at m/z 441, 443, 445, 447. Analysis calculated forC₂₀H₁₉N₂O₁Cl₃S₁.0.45H₂O: C, 53.39; H, 4.46; N, 6.23. Found: C, 53.37; H,4.46; N, 6.07.

EXAMPLE 9(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with1-acetylpiperazine. White solid; ¹H NMR (CDCl₃, 300 MHz) δ 2.15 (s, 3H),3.50-3.58 (m, 2H), 3.58-3.85 (m, 6H), 6.85 (d, J=15.3 Hz, 1H), 6.96 (d,J=8.7 Hz, 1H), 7.24-7.36 (m, 3H), 7.54 (dd, J=2.4 Hz, 1H), 7.61 (d,J=15.3 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 486,488, 490, 492. Analysis calculated for C₂₁H₁₉N₂O₂Cl₃S₁.0.85H₂O: C,51.99; H, 4.30; N, 5.77. Found: C, 52.03; H, 4.27; N, 5.67.

EXAMPLE 10(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with1-(2-pyridyl)piperazine. White solid; ¹H NMR (CDCl₃, 300 MHz) δ 3.59 (brm, 2H), 3.69 (br m, 2H), 3.78 (br m, 2H), 3.86 (br m, 2H), 6.64-6.72 (m,2H), 6.90 (d, J=15.6 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 7.22-7.25 (m, 2H),7.31 (dd, J=2.4, 8.7 Hz, 1H), 7.49-7.57 (m, 2H), 7.61 (d, J=15.6 Hz,1H), 7.62 (d, J=2.4 Hz, 1H), 8.19-8.24 (m, 1H). MS (DCI/NH₃) (M+H)⁺ atm/z 504, 506, 508, 510. Analysis calculated for C₂₄H₂₀N₃O₁Cl₃S₁: C,57.10; H, 3.99; N, 8.32. Found: C, 57.12; H, 4.06; N, 8.29.

EXAMPLE 11(2-(Hydroxymethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-mercaptobenzyl alcohol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with morpholine.White solid; ¹H NMR (CDCl₃, 300 MHz) δ 3.50-3.62 (br m, 6H), 3.65-3.74(br m, 2H), 4.54 (d, J=5.7 Hz, 2H), 5.33 (t, J=5.7 Hz, 1H), 6.62 (d,J=8.7 Hz, 1H), 7.28 (d, J=15.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.42 (d,J=15.0 Hz, 1H), 7.43 (dd, J=1.8, 8.7 Hz, 1H), 7.50 (dd, J=2.1, 8.7 Hz,1H), 7.55 (dd, J=2.1, 7.8 Hz, 1H), 7.68 (dd, J=1.5, 8.1 Hz, 1H), 8.02(d, J=2.1 Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 390, 392. Analysiscalculated for C₂₀H₂₀N₁O₃Cl₁S₁.0.09H₂O: C, 61.35; H, 5.20; N, 3.58.Found: C, 61.37; H, 5.48; N, 3.81.

EXAMPLE 12(2-(Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with morpholine.White solid; ¹H NMR (d⁶-DMSO, 300 MHz) δ 3.50-3.66 (br m, 6H), 3.66-3.79(br m, 2H), 7.05 (d, J=8.7 Hz, 1H), 7.26 (dd, J=2.1, 8.1 Hz, 1H), 7.33(dd, J=2.1, 8.1 Hz, 1H), 7.36 (d, J=15.6 Hz, 1H), 7.39 (dd, J=1.8, 12.0Hz, 1H), 7.45 (dd, J=1.8, 6.3 Hz, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.64(dd, J=2.1, 8.7 Hz, 1H), 7.80 (dd, J=2.8, 8.7 Hz, 1H), 8.09 (d, J=2.1Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 438, 440, 442.

EXAMPLE 13(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with1-hydroxyethylpiperazine. Colorless oil; ¹H NMR (CDCl₃, 300 MHz) δ2.85-3.20 (br m, 6H), 3.84-4.29 (m, 6H), 6.80 (d, J=15.3 Hz, 1H), 6.94(d, J=8.7 Hz, 1H), 7.72-7.38 (m, 3H), 7.50-7.56 (m, 1H), 7.56-7.62 (m,1H), 7.60 (d, J=15.3 Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 471, 473, 475,477.

EXAMPLE 14(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethoxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with1-[2-(2-hydroxyethoxy)ethyl]piperazine. Colorless oil; ¹H NMR (CDCl₃,300 MHz) δ 2.73 (br m, 6H), 3.58-3.68 (m, 2H), 3.68-4.00 (m, 8H), 6.84(d, J=15.3 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.20-7.34 (m, 3H), 7.54 (d,J=7.5 Hz, 1H), 7.58 (d, J=15.3 Hz, 1H), 7.58-7.65 (overlapping d, 1H).MS (DCIINH₃) (M+H)⁺ at m/z 515, 517, 519, 521.

EXAMPLE 15(2-(Bromophenl)[2-chloro-4-(E-((3-hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with3-hydroxymethylpiperidine. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.07 (d, J=17.7Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.63 (br d, J=7.7 Hz, 1H), 7.44 (d,J=7.0 Hz, 1H), 7.40 (br s, 2H), 7.35 (m, 1H), 7.25 (dd 7.7, 1.5, 1H),7.06 (dd, J=8.1 2.9, 1H), 4.57 (m, 1H), 4.45 (m, 1H), 4.16 (br m, 2H),1.2-1.8 (m, 8H). HRMS calculated for C₂₁H₂₁N₁O₂S₁Br₁Cl₁: 466.0243.Observed: 466.0247.

EXAMPLE 16(2-(Bromophenyl)[2-chloro-4-(E-((2-hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with2-hydroxymethylpiperidine. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.03 (m, 1H),7.79 (d, J=7.8 Hz, 1H), 7.61 (m, 1H), 7.30-7.45 (m, 4H), 7.23 (m, 1H),7.07 (m, 1H), 4.79 (m, 2H), 4.61 (m, 2H), 4.10 (m, 1H), 1.50 (m, 6H).HRMS calculated for C₂₁H₂₁N₁O₂S₁Br₁Cl₁: 466.0243. Observed: 466.0247.

EXAMPLE 17(2-(Bromophenl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with3-acetamidopyrrolidine. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.14 (m, 1H), 8.07(dd, J=9.8, 1.7 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.64 (dd, J=8.1, 1.7Hz, 1H), 7.25-7.47 (m, 4H), 7.10 (t, J=7.8 Hz, 1H), 7.03 (dd, J=8.1, 1.7Hz, 1H), 3.45-4.34 (m, 6H), 2.02 (m, 2H), 1.81 (ap d, J=1.4 Hz, 1H),HRMS calculated for C₂₁H₂₀N₂O₂S₁Br₁Cl₁: 479.0196. Observed: 479.0183.

EXAMPLE 18(2-(Bromophenyl)[2-chloro-4-(E-((4-hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with4-hydroxypiperidine. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.08 (d, J=1.7 Hz, 1H),7.80 (dd, J=8.0, 1.5 Hz, 1H), 7.63 (dd, J=8.3, 1.9 Hz, 1H), 7.44 (ap dd,J=7.5, 1.4 Hz, 2H), 7.40 (ap d, J=3.7 Hz 2H), 7.34 (dt, J=7.6, 1.8 Hz,1H), 7.25 (dd, J=7.5, 1.7 Hz 1H), 7.05 (d, J=8.1 Hz, 1H), 4.76 (br s,1H), 4.01 (m, 2H), 3.72 (m, 1H), 3.12 (m, 1H), 1.75 (m, 2H), 1.32 (m,2H). HRMS calculated for C₂₀H₁₉N₁O₂S₁Br₁Cl₁: 452.0087. Observed:452.0076.

EXAMPLE 19(2-(Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with piperidine.¹H NMR (DMSO-d₆, 300 MHz) δ 8.08 (d, J=1.7 Hz, 1H), 7.80 (dd, J=8.1, 1.4Hz, 1H), 7.63 (dd, J=8.1, 1.7 Hz, 1H), 7.44 (ap dd, J=7.6, 1.5 Hz, 1H),7.39 (ap d, J=4.8 Hz, 2H), 7.34 (dt, J=7.5, 1.6, 1H), 7.24 (dd, J=7.5,1.7, 1H), 7.05 (d, J=8.1 Hz, 1H), 3.65 (br m, 2H), 3.53 (br m, 2H), 1.62(br m, 2H), 1.50 (br m, 4H). HRMS calculated for C₂₀H₁₉N₁O₁S₁Br₁Cl₁:436.0130. Observed: 436.0122.

EXAMPLE 20(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with nipecoticacid. Colorless oil; ¹H NMR (CDCl₃, 300 MHz) δ 1.44-1.68 (br m, 1H),1.68-2.00 (br m, 2H), 2.51-2.67 (br m, 1H), 3.13-3.37 (br m, 1H),3.80-4.12 (br m, 1H), 4.30-5.00 (br m, 3H), 6.86 (d, J=15.3 Hz, 1H),6.99 (d, J=8.7 Hz, 1H), 7.16-7.24 (m, 2H), 7.29 (d, J=8.7 Hz, 1H),7.47-7.55 (m, 1H), 7.55 (d, J=15.3 Hz, 1H), 7.60 (br d, 1H). MS (APCI)(M+H)⁺ at m/z 470, 472, 474, 476.

EXAMPLE 21(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-4-fluoro-benzaldehyde, and 6-amino-1-hexanol with isonipecoticacid. Colorless oil; ¹H NMR (CDCl₃, 300 MHz) δ 1.68-1.85 (m, 2H),1.98-2.09 (m, 2H), 2.60-2.72 (m, 1H), 2.90-3.13 (br m, 1H), 3.17-3.38(br, m, 1H), 3.93-4.12 (br m, 1H), 4.38-4.59 (br m, 1H), 6.86 (d, J=15.3Hz, 1H), 6.99 (dd, J=8.7 Hz, 1H), 7.20-7.25 (m, 2H), 7.28 (dd, J=1.8,8.7Hz, 1H), 7.49-7.53 (m, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.60 (d, J=1.8 Hz,1H). MS (APCI) (M+H)⁺ at m/z 470, 472, 474, 476.

EXAMPLE 22(2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-3-fluoro-benzaldehyde, and 6-amino-1-hexanol with4-acetylhomopiperazine. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.10 (m, 1H), 7.81(d, J=7.7 Hz, 1H), 7.64 (m, 1H), 7.24-7.51 (m, 5H), 7.05 (m, 1H),3.39-3.77 (m, 8H), 1.97 (m, 3H), 1.68 (m, 2H). HRMS calculated forC₂₂H₂₂N₂O₂S₁Br₁Cl₁: 493.0352. Observed: 493.0352.

EXAMPLE 23(2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-3-fluoro-benzaldehyde, and 6-amino-1-hexanol withthiomorpholine. ¹H NMR (DMSO-d₆, 300 MHz) 68.10 (d, J=1.5 Hz, 1H), 7.80(d, J=8.5 Hz, 1H), 7.64 (dd, J=8.1, 1.5 Hz, 1H), 7.31-7.48 (m, 4H), 7.36(m, 1H), 7.26 (dd, J=8.1, 1.8 Hz, 1H), 7.05 (d J=8.1 Hz, 1H), 3.96 (m,2H), 3.82 (m, 2H), 2.62 (m, 4H). HRMS calculated for C₁₉H₁₇N₁O₁S₂Br₁Cl₁:455.9681. Observed: 455.9676.

EXAMPLE 24(2-Bromophenyl)[2-chloro-4-(E-((4-(1-benzimidazol-2-only)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide(2-Bromophenyl)[2-chloro-4 -(E-(( 4-([2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-3-fluoro-benzaldehyde, and 6-amino-1-hexanol with4-(1-benzimidazol-2-only)piperidine 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine. ¹H NMR (DMSO-d₆, 300MHz) δ 8.14 (d, J=1.5 Hz, 1H), 7.80 (dd, J=7.9, 1.3 Hz, 1H), 7.67 (dd,J=8.1, 1.8 Hz, 1H), 7.48 (ap s, 2H), 7.44 (dt, J=7.5, 1.2, 1H), 7.34(dt, J=7.6, 1.6, 1H), 7.26 (dd, J=7.7, 1.8 Hz, 1H), 7.22 (m, 1H), 7.06(d, J=8.1, 1H), 6.97 (ap d, J=2.6, 3H), 4.64 (m, 1H), 4.48 (m, 2H), 2.79(m, 2H), 2.29 (m, 2H), 1.78 (m, 2H). HRMS calculated forC₂₇H₂₃N₃O₂SBr₁Cl₁: 568.0461. Observed: 568.0477.

EXAMPLE 25(2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoguinolinyl)carbonylethenyl)phenyl]sulfide( 2-Bromophenyl)[2-chloro-4 -(E-((2-tetrahydroisoquinolinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-bromothiophenol,2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde3-chloro-3-fluoro-benzaldehyde, and 6-amino-1-hexanol withtetrahydroisoquinoline. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.12 (d, J=7.4 Hz,1H), 7.81 (dd, J=7.7. 1.1 Hz, 1H), 7.67 (dd, J=8.3, 1.3 Hz, 1H), 7.47(m, 2H), 7.43 (dd, J=7.5, 1.3 Hz, 2H), 7.34 (dt, J=7.6, 1.7 Hz, 1H),7.27 (d 7.7 Hz, 1H), 7.19 (m, 4H), 7.05 (d, J=8.1 Hz, 1H), 4.92 (s, 1H),4.72 (s, 1H), 3.95 (t, J=5.9 Hz, 1H), 3.78 (t, J=5.7 Hz, 1H), 2.89 (t,J=5.3 HZ, 1H), 2.83 (t, J=3.7, 1H). HRMS calculated forC₂₄H₁₉N₁O₂S₁Br₁Cl₁: 484.0138. Observed: 484.0128.

EXAMPLE 26(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonylethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-methylthiophenol,2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with1-acetylpiperazine. ¹H NMR (CDCl₃, 300 MHz) δ 7.79 (s, 1H); 7.63 (d,J=15.4 Hz, 1H); 7.51 (d, J=6.8 Hz, 1H); 7.41-7.33 (m, 3H); 7.28 (m, 1H);6.83 (d, J=15.4 Hz, 1H); 6.79 (d, J=6.8 Hz, 1H); 3.80-3.60 (m, 6H);3.57-3.50 (m, 2H); 2.34 (s, 3H); 2.14 (s, 3H). MS (ESI) m/z 919(2M+Na)⁺, 897 (2M+H)⁺, 471 (M+Na)⁺, 449 (M+H)⁺.

EXAMPLE 27(2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-methylthiophenol,2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol withmorpholine. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.79 (s, 1H); 7.63 (d, J=14.0Hz, 1H); 7.52 (d, J=7.6 Hz, 1H); 7.40-7.30 (m, 3H); 7.28 (m, 1H); 6.87(d, J=14.0 Hz, 1H); 6.84 (d, J=7.6 Hz, 1H); 3.73 (br s, 8H); 2.34 (s,3H). MS (ESI) m/z 837 (2M+Na)⁺, 815 (2M+H)⁺, 408 (M+H)⁺.

EXAMPLE 28(2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylamino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-methylthiophenol,2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with2-(1-morpholinyl)ethylamine. ¹H NMR (CDCl₃, 300 MHz) δ 7.80 (s, 1H);7.56 (d, J=15.8 Hz, 1H); 7.50 (d, J=8.1 Hz, 1H); 7.40-7.32 (m, 3H); 7.28(m, 1H); 6.79 (d, J=15.8 Hz, 1H); 6.40 (d, J=8.1 Hz, 1H); 3.75 (t, J=4.6Hz, 4H); 3.51 (q, J=5.5 Hz, 2H), 2.57 (t, J=5.8 Hz, 2H); 2.55-2.48 (m,4H); 2.34 (s, 3H ). MS (ESI) m/z 923 (2M+Na)⁺, 473 (M+Na)⁺, 451 (M+H)⁺.

EXAMPLE 29(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-methylthiophenol,2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with4-phenylpiperazine. ¹H NMR (CDCl₃, 300 MHz) δ 7.81 (s, 1H); 7.64 (d,J=16.0 Hz, 1H); 7.51 (d, J=8.2 Hz, 1H); 7.40-7.27 (m, 6H); 6.98-6.90 (m,4H); 6.80 (d, J=8.2 Hz, 1H); 3.88 (br s, 4H); 2.23 (br s, 4H); 2.34 (s,3H). MS (ESI) m/z 987 (2M+Na)⁺, 965 (2M+H)⁺, 505 (M+Na)⁺, 483 (M+H)⁺,451.

EXAMPLE 30(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide(2-Methylphenyl)[2-trifluoromethyl-4 -(E-(( 3 -(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-methylthiophenol,2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol with1-pyrrolidin-2-only)propylamine 3-( 2-oxopyrrolidin-1-yl)propylamine. ¹HNMR (CDCl₃, 300 MHz) δ 7.78 (s, 1H); 7.53 (d, J=15.6 Hz, 1H); 7.49 (d,J=7.2 Hz, 1H); 7.40-7.33 (m, 3H); 7.14 (m, 1H); 6.80 (d, J=8.2 Hz, 1H);6.43 (d, J=15.6 Hz, 1H); 3.41 (m, 4H); 3.32 (q, J=6.1 Hz, 2H); 2.43 (t,J=6.6 Hz, 2H); 2.34 (s, 3H), 2.08 (m, 2H), 1.75 (m, 2H). MS (ESI) m/z947 (2M+Na)⁺, 925 (2M+H)⁺, 4.85 (M+Na)⁺, 463 (M+H)⁺.

EXAMPLE 31(2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with 2-methylthiophenol,2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde4-fluoro-3-trifluoromethylbenzaldehyde, and 6-amino-1-hexanol withcyclopropylamine. ¹H NMR (CDCl₃, 300 MHz) δ 7.76 (s, 1H); 7.56 (d,J=15.4 Hz, 1H); 7.50 (d, J=8.4 Hz, 1H); 7.40-7.30 (m, 3H); 7.28 (m, 1H);6.88 (d, J=8.4 Hz, 1H); 6.30 (d, J=15.4 Hz, 1H); 5.70 (br s, 1H), 2.95(m, 1H); 2.34 (s, 3H); 0.85 (m, 2H); 0.57 (m, 2H). MS (ESI) m/z 777(2M+Na)⁺, 755 (2M+H)⁺, 400 (M+Na)⁺, 378 (M+H)⁺.

EXAMPLE 32(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfideEXAMPLE 32A1-Chloro-2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)benzene

To a stirred solution of trans-4-chloro-3-nitrocinnamic acid (1.50 g,6.59 mmol) and 1-acetylpiperazine (0.89 g, 6.94 mmol) in 20 mL of DMF atroom temperature was added EDAC (1.4 g, 7.30 mmol). The mixture was thenstirred at room temperature for 2 hours. TLC indicated the completeconsumption of the acid. Water was then added to quench the reaction andto precipitate out the product. Cinnamide was then collected throughfiltration and washed with cold water. The light yellow product wasdried in a vacuum oven overnight at 40° C. to give 2.04 g (6.03 mmol,91.6%) of the title compound.

EXAMPLE 32B(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

To a stirred solution of 4-chloro-3-nitro-cinnamide (275 mg, 0.814 mmol)from Example 32A in 1.0 mL of DMF was added potassium carbonate (169 mg,1.22 mmol), followed by the dropwise addition of 2,4-dichlorothiophenol(146 mg, 0.815 mmol). The mixture was then stirred at room temperaturefor 60 minutes. Completion of the reaction was indicated by the TLC.Water was then added to precipitate the product. Filtration, washingwith cold water, and drying in a vacuum oven afforded 350 mg (0.728mmol, 89%) of the titled title compound as a light yellow solid. ¹H NMR(d⁶-DMSO, 300 MHz) δ 2.05 (s, 3H), 3.42-3.50 (br m, 4H), 3.50-3.64 (brm, 2H), 3.64-3.79 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.44 (d, J=15.3Hz, 1H), 7.55 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d,J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.69 (d,J=1.8 Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 497, 499, 501. Analysiscalculated for C₂₁H₁₉N₃O₄Cl₂S₁.0.82H₂O: C, 50.94; H, 4.20; N, 8.49.Found: C, 50.91; H, 4.21; N, 8.69.

EXAMPLE 33(2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide(2,4-Dichlorophenyl)[2-nitro-4 -(E-(( 3 -(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 1-acetylpiperazine with1-(3-aminopropyl)-2-pyrrolidinone. Light-yellow powder; ¹H NMR (d⁶-DMSO,300 MHz) δ 1.64 (p, J=7.1 Hz, 2H), 1.91 (p, J=7.5 Hz, 2H), 2.21 (t,J=8.3 Hz, 2H), 3.15 (q, J=6.3 Hz, 2H), 3.21 (dd, J=9.9, 17.7 Hz, 2H),3.32 (overlapping t, J=8.4 Hz, 2H), 6.72 (d, J=15.6 Hz, 1H), 6.86 (d,J=8.7 Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.1 Hz, 1H),7.79 (dd, J=2.4, 8.7 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.4 Hz,1H), 8.18 (t, J=6.0 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H). MS (DCI/NH₃) (M+H)⁺at m/z 494, 496.

EXAMPLE 34(2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32B substituting 2,4-dichlorothiophenol with 2,3-dichlorothiophenol.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.42-3.50(br m, 4H), 3.50-3.64 (br m, 2H), 3.64-3.79 (br m, 2H), 6.88 (d, J=8.7Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.55 (t, J=7.65 Hz, 1H), 7.57 (d,J=15.6 Hz, 1H), 7.78 (dd, J=1.8, 8.1 Hz, 1H), 7.87 (dd, J=1.8, 8.1 Hz,1H), 7.95 (dd, J=2.7, 9.0 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H). MS (DCI/NH₃)(M+H)⁺ at m/z 497, 499, 501.

EXAMPLE 35(4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with 4-bromothiophenol.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.47 (brm, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m,1H), 6.90 (d, J=8.7 Hz, 1H), 7.43 (d, J=15.0 Hz, 1H), 7.54 (d, J=15.0Hz, 1H), 7.58 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.92 (dd,J=2.1, 9.0 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z507, 509.

EXAMPLE 36(4-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with p-thiocresol. Light-yellowpowder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.04 (s, 3H), 2.39 (s, 3H), 3.47 (brm, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 6.89 (d,J=8.7 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.40 (d,J=15.0 Hz, 1H), 7.53 (d, J=15.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.89(dd, J=2.1, 8.7 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H). MS (DCI/NH₃) (M+NH₄)⁺at m/z 443.

EXAMPLE 37(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 1-acetylpiperazine with tert-butyl piperazinecarboxylate. Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.42 (s,9H), 3.36 (overlapping m, 4H), 3.55 (br m, 2H), 3.70 (br m, 2H), 6.83(d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H),7.63 (dd, J=2.4, 8.4 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.92 (dd, J=2.4,8.7 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI)(M+H)⁺ at m/z 538, 540, 542.

EXAMPLE 38(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfideEXAMPLE 38A2,4-Dichlorophenyl[2-nitro-4-(E-((piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

Trifluoroacetic Acid Salt

The compound (100 mg, 0.186 mmol) from Example 37 was dissolved in 0.5mL of neat trifluoroacetic acid (TFA). The mixture was stirred at roomtemperature for 1 hour. The TFA was then removed under vacuum to givethe title compound (105 mg) as a yellow solid.

EXAMPLE 38B(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

To a stirred solution of piperazine TFA salt (35 mg, 0.067 mmol) fromExample 38A in 2.0 mL of CH₂Cl₂ was added Et₃N (23 μL, 0.17 mmol),4-dimethylaminopyridine (DMAP) (1.0 mg, 0.0082 mmol), and furyl chloride(8.0 μL, 0.080 mmol). The mixture was then stirred at room temperaturefor 30 minutes before the solvent was removed. The crude product waspurified with Gilson HPLC system, YMC C-18 column, 75×30 mm I.D., S-5μM, 120 Å, and a flow rate of 25 mL/min, λ=214, 245 nm; mobile phase A,0.05 M NH₄Oac NH₄ OAc, and B, CH₃CN; linear gradient 20-100% of B in 20minutes to give the title compound (24 mg, 67%) as a light-yellowpowder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 3.62-3.87 (br m, 8H), 6.66 (q, J=2.1Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 7.04 (d, J=3.3 Hz, 1H), 7.44 (d, J=15.3Hz, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.4, 8.1 Hz, 1H), 7.83 (d,J=8.4 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.92 (dd, J=2.1, 12.0 Hz, 1H),7.96 (d, J=2.1 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H). MS (APCI) (M+H)⁺ at m/z532, 534, 536.

EXAMPLE 39(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example38B substituting furoyl chloride with methanesulfonyl chloride.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.90 (s, 3H), 3.25 (brm, 4H), 3.68 (br m, 2H), 3.83 (br m, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.45(d, J=15.6 Hz, 1H), 7.56 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.7 Hz,1H), 7.83 (d, J=9.0 Hz, 1H), 7.93 (dd, J=2.1, 9.0 Hz, 1H), 7.95 (d,J=2.7 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H). MS (ESI) (M+H)⁺ at m/z 516, 518,520.

EXAMPLE 40(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example38B substituting furoyl chloride with 2-chloro-N,N-diethylacetamide.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.01 (t, J=7.2 Hz, 3H),1.13 (t, J=7.2 Hz, 3H), 2.46 (br m, 4H), 3.16 (s, 2H), 3.24 (q, J=7.2Hz, 2H), 3.37 (q, J=7.2 Hz, 2H), 3.56 (br m, 2H), 3.69 (br m, 2H), 6.83(d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H), 7.52 (d, J=15.3 Hz, 1H),7.62 (dd, J=2.4, 8.7 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.92 (dd, J=2.1,9.0 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.67 (d, J=2.1 Hz, 1H). MS (ESI)(M+NH₄)⁺ at m/z 573, 575, 577.

EXAMPLE 41(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example38B substituting furoyl chloride with N,N-diethylcarbamyl chloride.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.06 (t, J=6.9 Hz, 6H),3.12 (br m, 4H), 3.15 (q, J=6.9 Hz, 4H), 3.58 (br m, 2H), 3.72 (br m,2H), 6.83 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.53 (d, J=15.6Hz, 1H), 7.63 (dd, J=2.7, 9.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.92 (dd,J=2.4, 8.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H). MS(APCI) (M+H)⁺ at m/z 537, 539, 541.

EXAMPLE 42(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonylmethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example38B substituting CH₂CL₂ with CH₃CN as solvent, and furoyl chloride withtert-butyl bromoacetate. Light-yellow powder; ¹H NMR (CDCl₃, 300 MHz) δ1.47 (s, 9H), 2.70 (br m, 4H), 3.21 (s, 2H), 3.74 (br m, 2H), 3.82 (brm, 2H), 6.73 (d, J=8.7 Hz, 1H), 6.92 (d, J=15.0 Hz, 1H), 7.39 (dd,J=2.4, 8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.61 (d, J=15.0 Hz, 1H),7.62 (d, J=2.4 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 8.43 (br d, 1H). MS(APCI) (M+H)⁺ at m/z 552, 554, 556.

EXAMPLE 43(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfideEXAMPLE 43A(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-carbethoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example38B substituting furoyl chloride with ethyl oxalyl chloride.

EXAMPLE 43B(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

To a stirred solution of the ethyl ester (40 mg, 0.074 mmol) fromExample 43A in 2 mL of ethanol was added saturated LiOH (0.25 mL). Themixture was then stirred at room temperature for 2 hours. Water (2 mL)was then added to the reaction mixture, which was then acidified to pH=2with concentrated HCl. The precipitates were collected throughfiltration, washed with cold water, dried under vacuum to give thetitled title compound (30 mg, 79%) as a light yellow solid. ¹H NMR(d⁶-DMSO, 300 MHz) δ 3.52 (br m, 4H), 3.62 (br m, 2H), 3.76 (br m, 2H),6.84 (d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H), 7.56 (d, J=15.3 Hz,1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.93 (d,J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.70 (br d, 1H). MS (APCI)(M—COO)⁺ at m/z 466, 468, 470.

EXAMPLE 44(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example38A substituting compound from Example 37 with compound from Example 42.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 3.14 (s, 2H), 3.40(overlapping br m, 4H), 3.44 (br m, 1H), 3.51 (br m, 1H), 3.57 (br m,1H), 3.71 (br m, 1H), 6.82 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H),7.52 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.7 Hz, 1H), 7.83 (d, J=8.7Hz, 1H), 7.92 (dd, J=2.4, 8.7 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.68 (d,J=2.4 Hz, 1H). MS (APCI) (M+H)⁺ at m/z 496, 498, 500.

EXAMPLE 45(2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with o-thiocresol. Light-yellowpowder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.03 (s, 3H), 2.29 (s, 3H), 3.47 (brm, 4H), 3.53 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.83 (br m,1H), 6.64 (d, J=8.7 Hz, 1H), 7.40 (d, J=15.0 Hz, 1H), 7.36-7.42 (m, 1H),7.46-7.57 (m, 3H), 7.63 (d, J=6.9 Hz, 1H), 7.89 (dd, J=2.4, 9.0 Hz, 1H),8.66 (d, J=2.4 Hz, 1H). MS (APCI) (M+H)⁺ at m/z 426.

EXAMPLE 46(2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with 2-chlorothiophenol.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.47 (brm, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 3.73 (br m,1H), 6.75 (d, J=9.0 Hz, 1H), 7.43 (d, J=15.3 Hz, 1H), 7.54 (d, J=15.3Hz, 1H), 7.55 (dd, J=1.8, 8.1 Hz, 1H), 7.64 (t, J=1.8, 8.1 Hz, 1H), 7.76(d, J=1.8, 8.1 Hz, 1H), 7.82 (d, J=1.8, 8.1 Hz, 1H), 7.93 (dd, J=2.4,9.0 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI) (M+H)⁺ at m/z 446, 448,450.

EXAMPLE 47(2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with 2-aminothiophenol.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.47 (brm, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m,1H), 5.58 (s, 2H), 6.65 (td, J=1.5, 15.0 Hz, 1H), 6.72 (dd, J=1.5, 8.7Hz, 1H), 7.00 (dd, J=1.8, 8.7 Hz, 1H), 7.27 (t, J=1.5, 8.6 Hz, 1H), 7.36(dd, J=1.5, 8.7 Hz, 1H), 7.39 (d, J=15.3 Hz, 1H), 7.53 (d, J=15.3 Hz,1H), 7.89 (dd, J=1.8, 8.7 Hz, 1H), 8/64 (d, J=1.8 Hz, 1H). MS (APCI)(M+H)⁺ at m/z 427.

EXAMPLE 48(2-Hydroxymethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with 2-mercaptobenzyl alcohol.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.03 (s, 3H), 3.47 (brm, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.73 (br m,1H), 4.53 (d, J=5.7 Hz, 1H), 5.34 (t, J=5.7 Hz, 1H), 6.65 (d, J=8.7 Hz,1H), 7.40 (d, J=15.3 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.53 (d, J=15.3Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.87 (dd,J=2.1, 8.7 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H). MS (APCI) (M+NH₄)⁺ at m/z459.

EXAMPLE 49(2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with 2-ethylthiophenol.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.01 (t, J=7.65 Hz,3H), 2.04 (s, 3H), 2.69 (q, J=7.65 Hz, 2H), 3.47 (br m, 4H), 3.52 (br m,1H), 3.59 (br m, 1H), 3.67 (br m, 1H), 3.73 (br m, 1H), 6.64 (d, J=8.7Hz, 1H), 7.38 (dd, J=2.4, 7.5 Hz, 1H), 7.40 (d, J=15.6 Hz, 1H),7.50-7.61 (m, 3H), 7.53 (d, J=15.6 Hz, 1H), 7.89 (dd, J=2.4, 8.7 Hz,1H), 8.64 (d, J=2.4 Hz, 1H). MS (APCI) (M+Cl)⁻ at m/z 474, 476.

EXAMPLE 50(2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with 2-isopropylthiophenol.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.05 (d, J=6.9 Hz, 6H),2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67(br m, 1H), 3.72 (br m, 1H), 6.64 (d, J=8.4 Hz, 1H), 7.34-7.41 (m, 2H),7.39 (d, J=15.3 Hz, 1H), 7.52 (d, J=15.3 Hz, 1H), 7.56-7.73 (m, 2H),7.90 (dd, J=2.1, 8.7 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H). MS (APCI)(M+NH₄)³⁰ at m/z 471. Analysis calculated for C₂₄H₂₇N₃O₄S₁.0.21H₂O: C,63.03; H, 5.96; N, 9.13. Found: C, 63.03; H, 6.04; N, 9.19.

EXAMPLE 51(2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 2,4-dichlorothiophenol with 2-tert-butylthiophenol.Light-yellow powder; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.46 (s, 9H), 2.04 (s,3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H),3.73 (br m, 1H), 6.68 (d, J=8.7 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.39(d, J=15.3 Hz, 1H), 7.45-7.57 (m, 2H), 7.50 (d, J=15.3 Hz, 1H), 7.65 (d,J=8.1 Hz, 1H), 7.88 (dd, J=2.4, 8.7 Hz, 1H), 8.64 (d, J=2.4 Hz, 1H). MS(APCI) (M+NH₄)⁺ at m/z 485.

EXAMPLE 52(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl))2-propenyl)phenyl]sulfideEXAMPLE 52A 3′-Chloro-4′-[(2-chlorophenyl)thio]acetophenone

The title compound was prepared by the procedures described in Example1A substituting 2,4-dichlorothiophenol with 2-chlorothiophenol, and2-chlorobenzaldehyde with 4′-fluoro-3′-chloroacetophenone.

EXAMPLE 52B(2-Chlorophenyl)[2-chloro-4-(E-(1-ethoxycarbonyl)2-propenyl)phenyl]sulfide

To a stirred suspension of NaH (60% in mineral oil, 121 mg, 3.03 mmol)in 20 mL of anhydrous THF under nitrogen atmosphere was added triethylphosphonoacetate dropwise. After 20 minutes, the acetophenone (600 mg,2.02 mmol) from Example 52A in THF (5 mL) was added in one portion. Theresulting clear solution was then stirred at room temperature for 7hours. Reaction was then stopped, most of the solvent was evaporated,and the residue was partitioned between EtOAc (2×20 mL) and water. Thecombined organic layer was washed with water and brine, dried overNa₂SO₄, concentrated in vacuo. The crude product was purified usingsilica gel flash column chromatography eluting with 5-10% Et₂O inhexanes to give the (E)-isomer of the cinnamate (500 mg, 68%) as a whitesolid.

EXAMPLE 52C(2-Chlorophenyl)[2-chloro-4-(E-(1-carboxy)2-propenyl)phenyl]sulfide

A mixture of the cinnamate (500 mg, 1.37 mmol) from Example 52B in 5 mLof EtOH/THF (4:1) was stirred with sat. LiOH solution (0.50 mL) at 50°C. for 2 hours. The mixture was then acidified with 3N HCl and extractedwith CH₂Cl₂ (3×10 mL). The combined organic layer was dried over MgSO₄,concentrated under reduced pressure to give the titled title compound(450 mg, 97%) as a white solid.

EXAMPLE 52D(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl))2-propenyl)phenyl]sulfide

The title compound was prepared using the cinnamic acid from Example 52Cby the procedures described in Example 1C substituting 6-amino-1-hexanolwith 1-acetylpiperazine. White solid; ¹H NMR (CDCl₃, 300 MHz) δ2.10-2.20 (m, 3H), 2.25 (s, 3H), 3.40-3.80 (m, 8H), 6.28 (s, 1H), 7.00(d, J=8.7 Hz, 1H), 7.19-7.36 (m, 4H), 7.46-7.56 (m, 2H). MS (APCI)(M+NH₄)⁺ at m/z 466, 468, 470.

EXAMPLE 53(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfideEXAMPLE 53A(2-(1-Bromomethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

To a stirred solution of benzyl alcohol (195 mg, 0.32 mmol) from Example11 in 2.0 mL of anhydrous DMF was added LiBr (48 mg, 0.35 mmol). Themixture was then cooled in an ice-water bath, and PBr₃ (60 μL, 0.40mmol) was dropped in slowly. The ice bath was then removed and themixture was stirred at room temperature for 1 hour. Water was thenadded, the mixture was then partitioned between EtOAc and aqueousNaHCO₃. The aqueous layer was extracted with EtOAc once. The combinedorganic layer was washed with water and brine, dried over Na₂SO₄,concentrated on a rotavap. The crude bromide (230 mg) was used directlyfor the alkylation without purification.

EXAMPLE 53B(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

To a stirred solution of morpholine (10 μL, 0.11 mmol) in 0.5 mL ofCH₃CN was added Hunig base (23.7 μL, 0.14 mmol), followed by the bromide(40 mg, 0.091 mmol). The mixture was then stirred at room temperaturefor 2 hours. Solvent was then removed and the crude product was purifiedwith Gilson Preparative HPLC as described in Example 38B to give thetitled title compound as a white solid. ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.33(br t, 4H), 3.45 (br t, 4H), 3.50-3.65 (m, 6H), 3.56 (s, 2H), 3.65-3.80(br m, 2H), 6.74 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 1H), 7.35-7.41(m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.46 (td, J=2.4, 8.1 Hz, 1H), 7.52(dd, J=2.1, 8.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H).MS (DCI/NH₃) (M+H)⁺ at m/z 459, 461.

EXAMPLE 54(2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example53B substituting morpholine with 1-piperonylpiperazine. White solid; ¹HNMR (d⁶-DMSO, 300 MHz) δ 2.13-2.40 (br m, 8H), 3.28 (s, 2H), 3.49-3.64(br m, 6H), 3.54 (s, 2H), 3.70 (br m, 2H), 5.97 (s, 2H), 6.69 (dd,J=1.8, 8.1 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.79 (d, J=1.8 Hz, 1H), 6.81(d, J=8.1 Hz, 1H), 7.39 (d, J=15.3 Hz, 1H), 7.33-7.38 (m, 2H), 7.38-7.50(m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 8.00 (d, J=2.1Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 592, 594.

EXAMPLE 55(2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example53B substituting morpholine with N-isopropyl-1-piperazineacetamide.White solid; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.04 (d, J=6.3 Hz, 6H),2.20-2.42 (br m, 8H), 2.78 (s, 2H), 3.47-3.64 (br m, 6H), 3.56 (s, 2H),3.64-3.76 (br m, 2H), 3.85 (qd, J=6.3, 8.1 Hz, 1H), 6.73 (d, J=8.7 Hz,1H), 7.29 (d, J=15.6 Hz, 1H), 7.31-7.39 (m, 2H), 7.43 (d, J=15.6 Hz,1H), 7.45 (td, J=2.7, 6.3 Hz, 1H), 7.50 (dd, J=2.1, 8.7 Hz, 1H), 7.55(d, J=7.8 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z557, 559.

EXAMPLE 56(2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example53B substituting morpholine with ethyl sarcosinate hydrochloride. Whitesolid; ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.16 (t, J=7.2 Hz, 3H), 2.27 (s, 2H),3.30 (s, 2H), 3.51-3.66 (br m, 6H), 3.66-3.75 (br m, 2H), 3.78 (s, 2H),4.05 (q, J=7.2 Hz, 2H), 6.75 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 1H),7.33-7.38 (m, 2H), 7.42-7.50 (m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.53 (dd,J=2.1, 8.7 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H). MS(DCI/NH₃) (M+H)⁺ at m/z 489, 491.

EXAMPLE 57(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

To a stirred solution of the alcohol (368 mg, 0.94 mmol) from Example 11in 5 mL of anhydrous acetonitrile was added activated 4 Å molecularsieves, TPAP (3.3 mg, 0.0094 mmol), and NMO (110 mg, 1.03 mmol). Themixture was then stirred at room temperature for 3 hours. The reactionmixture was then quenched with dimethyl sulfide (100 μL). The crudeproduct was filtered through celite, washed with acetonitrile, andcondensed in vacuo. The titled title compound was purified by silica gelcolumn chromatography to give a white solid (216 mg, 59%). ¹H NMR(d⁶-DMSO, 300 MHz) δ 3.60 (br m, 6H), 3.73 (br m, 2H), 7.00 (d, J=8.4Hz, 1H), 7.40 (d, J=15.3 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.51 (d,J=15.3 Hz, 1H), 7.52 (td, J=1.8, 8.1 Hz, 1H), 7.61 (td, J=1.8, 8.1 Hz,1H), 7.71 (dd, J=2.1, 8.4 Hz, 1H), 8.02 (dd, J=2.1, 8.4 Hz, 1H), 8.14(d, J=2.1 Hz, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 388, 390.

EXAMPLE 58(2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example53B substituting morpholine with 1-formyl piperazine. White solid; ¹HNMR (d⁶-DMSO, 300 MHz) δ 2.20-2.32 (m, 6H), 2.74 (br m, 2H), 3.48 (s,2H), 3.59 (m, 6H), 3.70 (br m, 2H), 6.74 (d, J=8.7 Hz, 1H), 7.29 (d,J=15.6 Hz, 1H), 7.35-7.41 (m, 2H), 7.42 (d, J=15.6 Hz, 1H), 7.45-7.52(m, 3H), 7.98 (d, J=2.1, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 486, 488.

EXAMPLE 59(2-(E-((1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

A mixture of bromide (80 mg, 0.18 mmol) from Example 12,acryloylmorpholine (33 mg, 0.23 mmol), Pd(Oac)₂ (2.0 mg, 0.009 mmol),P(o-tolyl)₃ (17 mg, 0.056 mmol), Et₃N (39 μL, 0.27 mmol), and anhydrousDMF (1.0 mL) in a pressure tube was flushed with nitrogen for 5 minutesbefore it was capped and heated at 110° C. over night overnight. TLCindicated almost complete consumption of the starting bromide. Thereaction mixture was then allowed to cool down to room temperature, andpartitioned between EtOAc and water. The aqueous layer was extractedonce with EtOAc. The combined organic layer was washed with water andbrine, dried over Na₂SO₄, and condensed under reduced pressure. Thecrude product was purified with Gilson Preparative HPLC as described inExample 38B to give the titled title compound as a light-brown solid (35mg, 39%). ¹H NMR (d⁶-DMSO, 300 MHz) δ 3.43-3.88 (m, 16H), 6.58 (d, J=8.7Hz, 1H), 7.30 (d, J=15.3 Hz, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.47-7.64 (m,4H), 7.86 (d, J=15.3 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.14 (d, J=7.5 Hz,1H). MS (DCI/NH₃) (M+NH₄)⁺ m/z 516, 518. Analysis calculated forC₂₆H₂₇N₂O₄Cl₁S₁.0.46H₂O: C, 61.56; H, 5.55; N, 5.21. Found: C, 61.56; H,5.50; N, 5.43.

EXAMPLE 60(2-Formylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example57 substituting compound from Example 11 with compound from Example 48.Yellow solid; ¹H NMR (d⁶-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.47 (br m, 4H),3.52 (br m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 6.85(d, J=8.4 Hz, 1H), 7.44 (d, J=15.6 Hz, 1H), 7.55 (d, J=15.6 Hz, 1H),7.61 (d, J=7.5 Hz, 1H), 7.73 (t, J=7.5 Hz, 1H), 7.80 (td, J=2.4, 7.5 Hz,1H), 7.92 (dd, J=2.1, 9.0 Hz, 1H), 8.04 (dd, J=2.4, 7.5 Hz, 1H), 8.66(d, J=2.1 Hz, 1H), 10.29 (s, 1H). MS (APCI) (M+Cl)⁻ at m/z 474, 476.

EXAMPLE 61(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide,N,N-dimethyl hydrazone

A mixture of the aldehyde (20 mg, 0.052 mmol) from Example 57,1,1-dimethyl hydrazine (3.9 μL, 0.052 mmol) in 0.5 mL of EtOH with atiny amount of AcOH was stirred at room temperature over nightovernight. The solvent was then removed and the product was purified bypreparative TLC to give the titled title compound (20 mg, 90%) as awhite solid. ¹H NMR (CDCl₃, 300 MHz) δ 2.91 (s, 6H), 3.55-3.82 (br m,8H), 6.64 (d, J=8.7 Hz, 1H), 6.76 (d, J=15.3 Hz, 1H), 7.05 (dd, J=1.8,8.7 Hz, 1H), 7.26 (td, J=1.8, 7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H),7.47-7.57 (m, 2H), 7.54 (m, 2H), 8.04 (dd, J=1.8, 8.7 Hz, 1H). MS(DCI/NH₃) (M+H)⁺ at m/z 430, 432, 434, 436.

EXAMPLE 62(2-((3-(1-Morpholinyl)propyl)-1-amino)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

A mixture of bromide (60 mg, 0.14 mmol) from Example 12,aminopropylmorpholine (24 μL, 0.17 mmol), Pd₂(dba)₃ (1.2 mg, 0.0013mmol), BINAP (2.5 mg, 0.004 mmol), NaOt-Bu (19 mg, 0.20 mmol),18-crown-6 (50 mg, 0.20 mmol), and anhydrous toluene (1 mL) in apressure tube was flushed with nitrogen for 3 minutes before it wascapped and heated at 80° C. over night overnight. The reaction was thenstopped, and allowed to cool down to room temperature. The reactionmixture was partitioned between EtOAc and water, and the aqueous layerwas extracted once with EtOAc. The combined organic layer was thenwashed with water and brine, dried over Na₂SO₄, and condensed underreduced pressure. The crude product was purified with Gilson PreparativeHPLC as described in Example 38B to give the titled title compound as alight-brown oil (30 mg, 44%). ¹H NMR (d⁶-DMSO, 300 MHz) δ 1.62 (quintet,J=6.5 Hz, 2H), 2.15-2.26 (m, 8H), 3.17 (q, J=6.5 Hz, 2H), 3.22-3.76 (m,12H), 3.50 (t, J=6.5 Hz, 2H), 5.72 (t, J=5.7 Hz, 1H), 6.47 (d, J=8.7 Hz,1H), 6.68 (t, J=7.2 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 7.26 (d, J=15.6 Hz,1H), 7.35-7.42 (m, 2H), 7.43 (d, J=15.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H),7.49 (d, J=8.4 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS (APCI) (M+H)⁺ at m/z502, 504.

EXAMPLE 63(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide(2,4-Dichlorophenyl)[2-bromo-4 -(E-(( 3 -(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide EXAMPLE63A(2,4-Dichlorophenyl)[2-amino-4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonylethenyl)phenyl]sulfide( 2,4-Dichlorophenyl)[2-amino-4 -(E-(( 3 -(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide

A mixture of nitro compound (780 mg, 1.58 mmol) from Example 33, SnCl₂(1.50 g, 7.91 mmol) in 25 mL of anhydrous EtOH was refluxed undernitrogen atmosphere for 90 minutes. The reaction was then allowed tocool down to room temperature, quenched with sat. NaHCO₃, and extractedwith EtOAc (2×50 mL). The combined organic layer was washed with waterand brine, dried over Na₂SO₄, and condensed in vacuo to give the crudeaniline as a yellowish brown solid, which was converted to the bromidewithout purification.

EXAMPLE 63B(2,4-Dichlorophenyl)[2-bromo4-(E-((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide(2,4-Dichlorophenyl)[2-bromo-4 -(E-(( 3 -(2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide

To a stirred solution of t-butyl nitrite (57 μL, 0.48 mmol), CrBr₂ (87mg, 0.39 mmol) in 2.0 mL of CH₃CN at room temperature was added asolution of aniline from Example 63A (150 mg, 0.323 mmol) in 1.0 mL ofCH₃CN. The dark green solution was then heated at 65° C. under nitrogenatmosphere for 90 minutes. The reaction mixture was then allowed to cooldown to room temperature, and partitioned between EtOAc and 3N HCl. Theorganic layer was then washed with brine, dried over Na₂SO₄, andcondensed in vacuo. The crude product was then purified with GilsonPreparative HPLC as described in Example 38B to give the titled titlecompound as a light-brown solid (50 mg, 29%). Colorless oil; ¹H NMR(d⁶-DMSO, 300 MHz) δ 1.63 (quintet, J=7.2 Hz, 2H), 1.91 (quintet, J=8.4Hz, 2H), 2.22 (t, J=8.4 Hz, 2H), 3.09-3.47 (m, 6H), 6.67 (d, J=15.3 Hz,1H), 7.07 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.38 (d, J=15.3 Hz,1H), 7.50 (dd, J=2.4, 8.7 Hz, 1H), 7.57 (dd, J=2.1, 8.4 Hz, 1H), 7.86(d, J=2.4 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 8.13 (t, J=6.0 Hz, 1H). MS(ESI) (M+H)⁺ at m/z 527, 529, 531, 533.

EXAMPLE 64(2,4-Dichlorophenyl)[2-bromo-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfideEXAMPLE 64A[1-Fluoro-2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)benzene

The title compound was prepared by the procedures described in Example59 substituting the bromide from Example 12 with2-fluoro-5-bromobenzaldehyde.

EXAMPLE 64B(2,4-Dichlorophenyl)[2-bromo-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example32 substituting 4-chloro-3-nitro-cinnamide with the compound fromExample 64A. White solid: ¹H NMR (d⁶-DMSO, 300 MHz) δ 3.60 (br m, 6H),3.71 (br m, 2H), 6.82 (d, J=8.7 Hz, 1H), 7.35 (d, J=15.6 Hz, 1H), 7.54(d, J=15.6 Hz, 1H), 7.55 (dd, J=2.4, 8.7 Hz, 1H), 7.61 (d, J=8.7 Hz,1H), 7.86 (dd, J=2.4, 8.4 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 8.41 (d,J=2.1 Hz, 1H), 10.19 (s, 1H). MS (DCI/NH₃) (M+H)⁺ at m/z 422, 424, 426,428.

EXAMPLE 65(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfideEXAMPLE 65A(2-Carbomethoxyethyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

The title compound was prepared by the procedures described in Example 1substituting 2,4-dichlorothiophenol with methyl 3-mercaptopropionate,and 6-amino-1-hexanol with 1-acetyl piperazine.

EXAMPLE 65B(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide

To a stirred solution of the compound (105 mg, 0.26 mmol) from Example65A in 2 mL of THF under nitrogen atmosphere at 0° C. was added t-BuOKsolution (1.0M, 281 μL, 0.29 mmol). Light orange precipitates appearedimmediately. After completion of the addition, the reaction mixture wasstirred at room temperature for 1 hour before the solvent was removed ona rotavap under reduced pressure.

The yellow thiolate thus obtained was dissolved in 0.5 mL of DMF, and2,3-dichlorobenzaldehyde was then added. The mixture was then heated at80° C. under nitrogen for 2 hours. Reaction was then stopped and thesolvent was removed under vacuum. The crude product was purified withGilson Preparative HPLC as described in Example 38B to give the titledtitle compound as a white solid (25 mg, 21%). ¹H NMR (CDCl₃, 300 MHz) δ2.05 (s, 3H), 3.48-3.58 (m, 2H), 3.58-3.84 (m, 6H), 6.53 (d, J=8.7 Hz,1H), 6.80 (d, J=15.3 Hz, 1H), 7.19 (dd, J=1.8, 8.7 Hz, 1H), 7.51-7.62(m, 2H), 7.60 (d, J=15.3 Hz, 1H), 7.84 (dd, J=1.8, 8.4 Hz, 1H), 7.99(dd, J=1.8, 8.4 Hz, 1H). MS (APCI) (M+NH₄)⁺ at m/z 480, 482, 484.

Compounds that antagonize the interaction between ICAM-1 and LFA-1 canbe identified, and their activities quantitated, using both biochemicaland cell-based adhesion assays. A primary biochemical assay measures theability of the compound in question to block the interaction between theintegrin LFA-1 and its adhesion partner ICAM-1, as described below:

ICAM-1/LFA-1 Biochemical Interaction Assay

In the biochemical assay, 100 μL of anti-LFA-1 antibody (ICOSCorporation) at a concentration of 5 μg/ml mL in Dulbecco'sphosphate-buffered saaline (D-PBS) is used to coat wells of a 96-wellmicrotiter plate overnight at 4° C. The wells are were then washed twicewith wash buffer (D-PBS w/o Ca⁺⁺ or Mg⁺⁺, 0.05% Tween 20) and blocked byaddition of 200 μL of D-PBS, 5% fish skin gelatin. Recombinant LFA-1(100 μL of 0.7 μg/ml mL, ICOS Corporation) in D-PBS is was then added toeach well. Incubation continues continued for 1 hour at room temperatureand the wells are were washed twice with wash buffer. Serial dilutionsof compounds being assayed as ICAM-1/LFA-1 antagonists, were prepared as10 mM stock solutions in dimethyl sulfoxide (DMSO), are were diluted inD-PBS, 2 mM MgCl₂, 1% fish skin gelatin and 50 μL of each dilution wasadded to duplicate wells. This is was followed by the addition of 50 μLof 0.8 μg/ml mL biotinylated recombinant ICAM-1/Ig (ICOS Corporation) tothe wells and the plates are were incubated at room temperature for 1hour. The wells are were then washed twice with wash buffer and 100 μLof Europium-labeled Streptavidin (Wallac Oy) diluted 1:100 in Delfiaassay buffer (Wallac Oy), are was then added to the wells. Incubationproceeds proceeded for 1 hour at room temperature. The wells are werewashed eight times with wash buffer and 100 μL of enhancement solution(Wallac Oy, cat. No. 1244-105) are was added to each well. Incubationproceeds proceeded for 5 minutes with constant mixing. Time-resolvedfluorimetry measurements are were made using the a Victor 1420Multilabel Counter (Wallac Oy) and the percent inhibition of eachcandidate compound is was calculated using the following equation:$\text{\%~~inhibition} = {100 \times \left\{ {1 - \frac{\text{average~~OD~~w/compound~~minus~~background}}{\text{average~~OD~~w/o~~compound~~minus background}}} \right\}}$where “background” refers to wells that are were not coated withanti-LFA-1 antibody.

Compounds of the present invention exhibit exhibited inhibitory activityin the above assay as follows:

Compound % inhibition of Example @ 4 μM 1 75 2 73 3 75 4 72 5 73 6 85 787 8 74 9 93 10 79 11 87 12 90 13 79 14 82 15 88 16 86 17 84 18 86 19 9320 82 21 80 22 90 23 90 24 80 25 82 26 94 27 94 28 87 29 84 30 93 31 9232 92 33 91 34 91 35 89 36 90 37 91 38 91 39 86 40 90 41 83 42 56 43 8244 78 45 88 46 87 47 82 48 89 49 93 50 94 51 84 52 86 53 87 54 86 55 8256 83 57 90 58 80 59 92 60 95 61 88 62 92 63 82 64 81 65 86

Biological relevant activity of the compounds in this invention isconfirmed using a cell-based adhesion assay, which measures theirability to block the adherence of JY-8 cells (a human EBV-trasformed Bcell line expressing LFA-1 on its surface) to immobilized ICAM-1, asfollows:

ICAM-1/JT-8 Cell Adhesion Assay

For measurment measurement of inhibotory inhibitory activity in thecell-based adhesion assay, 96-well microtiter plates are were coatedwith 70 μL of recombinat recombinant ICAM-1/Ig (ICOS Corporation) at aconcentration of 5 μg/mL in D-PBS w/o without Ca^(++ or Mg++ or Mg) ⁺⁺overnight at 4° C. The wells are were then washed twice with D-PBS andblocked by addition of 200 μL of D-PBS, 5% fish skin gelatin byincubation for 1 hour at room temperature. Fluorescent tagged JY-8 cells(a human EBV-transformed B cell line expresing expressing LFA-1 on itssurface; 50 μL at 2×10⁶ cells/ml mL in RPMI 1640/1% fetal bovene bovineserum) are were added to the wells. For fluorescent labelind labellingof JY-8 cells, 5×10⁶ cells washed once in RPMI 1640 are were resuspendedin 1 mL of RPMI 1640 containing 2 μM Calceiun AM (Molecular Probes), arewere incubated at 37° C. for 30 minutes, and washed once withRPMI-1640/1% fetal bovine serum. Dilutions of compounds to be assayedfor ICAM-1/LFA-1 antagonistic activity are were prepared in RPMI-1640/1%fetal bovine serum from 10 mM stock solutions in DMSO and 50 μL are wereadded to duplicate wells. Microtiter plates are were incubated for 45minutes at room temperature and the wells are were washed gently oncewith RPMI-1640/1% fetal bovine serum. Fluorescent intensity is wasmeasured in a fluorescent plate reader with an excitation wavelength at485 nM and an emission wavelength at 530 nM. The percent inhibition of acandidate compound at a given concentration is was calculated using thefollowing equation:$\text{\%~~inhibition} = {100 \times \left\{ {1 - \frac{\text{average~~OD~~w/compound}}{\text{average~~OD~~w/o~~compound}}} \right\}}$and these concentration/inhibition data are were used to generate doesresponse curves, from which IC₅₀ values are were derived. Compounds ofthe present invention exhibit exhibited blocking activity in the aboveassay as follows:

Compound of Example IC₅₀ nM 1 2,100 2 13,000 3 2,500 4 680 5 2,900 6 6607 1,200 8 2,900 9 130 10 1,500 11 260 12 360 13 1,100 14 790 15 140 16300 17 5,800 18 130 19 450 20 3,300 21 520 22 200 23 600 24 8,000 2511,000 26 110 27 160 28 370 29 160 30 250 32 190 32 45 33 300 34 70 35430 36 320 37 140 38 250 39 250 40 280 41 110 42 520 43 100 44 70 45 5046 60 47 370 48 200 49 20 50 10 51 690 52 420 53 700 54 360 55 100 56510 57 220 58 1,600 59 200 60 30 61 540 62 340 63 850 65 1,200

Compounds of the present invention have been demonstrated to act viainteraction with the integrin LFA-1, specifically by binding to theinteraction domain (I-domain), which is known to be critical for theadhesion of LFA-1 to a variety of cell adhesion molecules. As such, itis expected that these compounds should block the interaction of LFA-1with other CAM's. This has in fact been demonstrated for the case ofICAM-3. Compounds of the present invention may be evaluated for theirability to block the adhesion of JY-8 cells (a human EBV-transformed Bcell line expressing LFA-1 on its surface) to immobilized ICAM-3, asfollows:

ICAM-3/JY-8 Cell Adhesion Assay

For measurement of inhibitory activity in the cell-based adhesion assay,96-well microtiter plates are were coated with 50 μL of recombinantICAM-3/Ig (ICOS Corporation) at a concentration of 10 μg/mL in D-PBS w/owithout Ca⁺⁺ or Mg⁺⁺ overnight at 4° C. The wells are were then washedtwice with D-PBS, blocked by addition of 100 μL of D-PBS, 1% bovineserum albumin (BSA) by incubation for 1 hour at room temperature, andwashed once with RPMI-1640/5% heat-inactivated fetal bovine serum(adhesion buffer). Dilutions of compounds to be assayed for ICAM-3/LFA-1antagonistic activity are were prepared in adhesion buffer from 10 mMstock solutions in DMSO and 100 μL are were added to duplicate wells.JY-8 cells (a human EBV-transformed B cell line expressing LFA-1 on itssurface; 100 μL at 0.75×10⁶ cells/ml mL in adhesion buffer) are werethen added to the wells. Microtiter plates are were incubated for 30minutes at room temperature; the adherent cells are were then fixed with50 μL of 14% glutaraldehyde/D-PBS and were incubated for an additional90 minutes. The wells are were washed gently with dH₂O; 50 μL of dH₂O iswas added, following followed by 50 μL of 1% crystal violet. After 5minutes the plates are were washed 3× times with dH₂O; 75 μL of dH₂O and225 μL of 95% EtOH are were added to each well to extract the crystalviolet from the cells. Absorbance is was measured at 570 nM in an ELISAplate reader. The percent inhibition of a candidate compound is wascalculated using the following equation.$\text{\%~~inhibition} = {100 \times \left\{ {1 - \frac{\text{average~~OD~~w/compound}}{\text{average~~OD~~w/o~~compound}}} \right\}}$Compounds of the present invention exhibit exhibited blocking activityin the above assay as follows. :

Compound % inhibition Of Example @ 0.6 μM 9 100 12 100 15 100 16 100 17100 18 100 26 100 27 100 30 100 32 100 34 100 35 100 41 100 45 100 46100 49 100 50 100 54 100 59 100 60 100 62 100

The ability of the compounds of this invention to treat arthritis can bedemonstrated in a murine collagen-induced arthritis model according tothe method of Kakimoto, et al., Cell Immunol 142: 326-337, 1992, in arat collagen-induced arthritis model according to the method ofKnoerzer, et al., Toxicol Pathol 25:13-19, 1997, in a rat adjuvantarthritis model according to the method of Halloran, et al., ArthitisArthritis Rheum 39: 810-819, 1996, in a rat streptococcal cellwall-induced arthritis model according to the method of Schimmer, etal., J. Immunol 160: 1466-1477, 1998, or in a SCID-mouse humanrheumatoid arthritis model according to the method of Oppenheimer-Markset al., J Clin. Invest 101: 1261-1272, 1998.

The ability of the compounds of this invention to treat Lyme arthritiscan be demonstrated according to the method of Gross et al., Science281, 703-706, 1998.

The ability of compounds of this invention to treat asthma can bedemonstrated in a murine allergic asthma model according to the methodof Wegner et al., Science 247:456-459, 1990, or in a murine non-allergicasthma model according to the method of Bloemen et al., Am J Respir CritCare Med 153:521-529, 1996.

The ability of compounds of this invention to treat inflammatory lunginjury can be demonstrated in a murine oxygen-induced lung injury modelaccording to the method of Wegner et al., Lung 170:267-279, 1992, in amurine immune complex-induced lung injury model according to the methodof Mulligan et al., J Immunol 154:1350-1363, 1995, or in a murineacid-induced lung injury model according to the method of Nagase, etal., Am J Respir Crit Care Med 154:504-510, 1996.

The ability of compounds of this invention to treat inflammatory boweldisease can be demonstrated in a rabbit chemical-induced colitis modelaccording to the method of Bennet et al., J Pharmacol Exp Ther280:988-1000, 1997.

The ability of compounds of this invention to treat autoimmune diabetescan be demonstrated in an NOD mouse model according to the method ofHasagawa et al., Int Immunol 6:831-838, 1994, or in a murinestreptozotocin-induced diabetes model according to the method of Herroldet al., Cell Immunol 157:489-500, 1994.

The ability of compounds of this invention to treat inflammatory liverinjury can be demonstrated in a murine liver injury model according tothe method of Tanaka et al., J Immunol 151:5088-5095, 1993.

The ability of compounds of this invention to treat inflammatoryglomerular injury can be demonstrated in a rat nephrotoxic serumnephritis model according to the method of Kawasaki, et al., J Immunol150:1074-1083, 1993.

The ability of compounds of this invention to treat radiation-inducedenteritis can be demonstrated in a rat abdominal irradiation modelaccording to the method of Panes et al., Gastroenterology 108:1761-1769,1995.

The ability of compounds of this invention to treat radiationpneumonitis can be demonstrated in a murine pulmonary irradiation modelaccording to the method of Hallahan et al., Proc Natl Acad Sci USA94:6432-6437, 1997.

The ability of compounds of this invention to treat reperfusion injurycan be demonstrated in the isolated rat heart according to the method ofTamiya et al., Immunopharmacology 29(1): 53-63, 1995, or in theanesthetized dog according to the model of Hartman et al., CardiovascRes 30(1): 47-54, 1995.

The ability of compounds of this invention to treat pulmonaryreperfusion injury can be demonstrated in a rat lung allograftreperfusion injury model according to the method of DeMeester et al.,Transplantation 62(10): 1477-1485, 1996, or in a rabbit pulmonary edemamodel according to the method of Horgan et al., Am J Physiol 261(5):H1578-H1584, 1991.

The ability of compounds of this invention to treat stroke can bedemonstrated in a rabbit cerebral embolism stroke model according themethod of Bowes et al., Exp Neurol 119(2): 215-219, 1993, in a ratmiddle cerebral artery ischemia-reperfusion model according to themethod of Chopp et al., Stroke 25(4): 869-875, 1994, or in a rabbitreversible spinal cord ischemia model according to the method of Clarket al., Neurosurg 75(4): 623-627, 1991.

The ability of compounds of this invention to treat peripheral arteryocclusion can be demonstrated in a rat skeletal muscleischemia/reperfusion model according to the method of Gute et al., MolCell Biochem 179: 169-187, 1998.

The ability of compounds of this invention to treat graft rejection canbe demonstrated in a murine cardiac allograft rejection model accordingto the method of Isobe et al., Science 255: 1125-1127, 1992, in a murinethyroid gland kidney capsule model according to the method of Talento etal., Transplantation 55: 418-422, 1993, in a cynomolgus monkey renalallograft model according to the method of Cosimi et al., J Immunol 144:4604-4612, 1990, in a rat nerve allograft model according to the methodof Nakao et al., Muscle Nerve 18: 93-102, 1995, in a murine skinallograft model according to the method of Gorczynski and Wojcik, JImmunol 152: 2011-2019, 1994, in a murine corneal allograft modelaccording to the method of He et al., Opthalmol Vis Sci 35: 3218-3225,1994, or in a xenogeneic pancreatic islet cell transplantation modelaccording to the method of Zeng et al., Transplantation 58:681-689,1994.

The ability of compounds of this invention to treat graft-vs.-hostdisease (GVHD) can be demonstrated in a murine lethal GVHD modelaccording to the method of Haming et al., Transplantation 52:842-845,1991.

The ability of compounds of this invention to treat cancers can bedemonstrated in a human lymphoma metastasis model (in mice) according tothe method of Aoudjit et al., J Immunol 161:2333-2338, 1998.

1. A compound of the formula I:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug thereof of a compound of formula I, wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, and with the proviso that at least one of R₁ or and R₃ is a “cis-cinnamide” or a “trans-cinnamide”, defined as

wherein R₈ and R₉ are each independently selected from a. hydrogen, and b. alkyl, c. carboxy alkyl, d. alkylaminocarbonyl alkyl, and e. dialkylaminocarbonyl alkyl, and R₁₀ and R₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or where NR₁₀R₁₁ is R₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4) cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8) heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11) hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14) carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17) aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20) carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23) alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26) alkylsulfonyl, and wherein Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where substitutions the substituents are each independently selected from a. hydrogen, ba. halogen, cb. alkyl, dc. aryl, ed. haloalkyl, fe. hydroxy, gf. alkoxy, hg. alkoxycarbonyl, ih. alkoxyalkoxy, ji. hydroxyalkyl, kj. aminoalkyl, lk. alkyl(alkoxycarbonylalkyl)aminoalkyl, ml. unsubstituted heterocyclylalkyl, nm. substituted heterocyclylalkyl, on. carboxaldehyde, po. carboxaldehyde hydrazone, qp. carboxamide, rq. alkoxycarbonyl alkyl, sr. hydroxycarbonylalkyl (carboxyalkyl), ts. cyano, ut. amino, vu. heterocyclylalkylamino, and wv. “trans-cinnamide”, or a pharmaceutically-acceptable salt or prodrug thereof. subject to the proviso that when R₃ is a “cis-cinnamide” or a “trans-cinnamide,” as defined above, one or more than one of the following conditions is fulfilled: (A) Ar is an unsubstituted heteroaryl group, a substituted heteroaryl group, or a substituted aryl group wherein when Ar is a pyridyl group, Ar is substituted and Ar is not substituted by only one alkyl group; (B) one or more than one of R₁ , R ₂ , R ₄ , and R ₅ , as defined above, are other than hydrogen; and (C) R₁₀ and R ₁₁ are taken together with N to form a substituted or unsubstituted heterocyclyl group, as defined above.
 2. A compound according to claim 1 wherein R₁ is a “cis-cinnamide” or a “trans-cinnamide”, and R₃ is hydrogen.
 3. A compound according to claim 1 wherein R₃ is a “cis-cinnamide” or a “trans-cinnamide”, and R₁ is hydrogen .
 4. A compound according to claim 1 wherein R₃ is a “cis-cinnamide” or a “trans-cinnamide”, and one or more than one of R₁, R₈, and R₉ are each hydrogen.
 5. A compound according to claim 4 wherein R₃ is a “cis-cinnamide”.
 6. A compound according to claim 4 wherein R₃ is a “trans-cinnamide”.
 7. A compound according to claim 1 wherein R₃ is a “cis-cinnamide” or a “trans-cinnamide”, and R₁, R₂, and R₄ are each independently hydrogen or alkyl; and R₅ is selected from halogen, haloalkyl, and nitro.
 8. A compound according to claim 4 wherein Ar is aryl, a substituted aryl group, an unsubstituted heteroaryl group, or a substituted heteroaryl group.
 9. A compound according to claim 4 wherein one or both of R₁₀ and R₁₁ are each independently selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, hydroxyalkyl, and heterocyclylalkyl.
 10. A compound according to claim 4 wherein NR₁₀R₁₁ is R₁₀ and R ₁₁ are taken together with N to form an unsubstituted heterocyclyl group or a substituted heterocyclyl group.
 11. A compound according to claim 8 4 wherein Ar is selected from substituted phenyl, 1,3-benzimidazol-2-one, 1,4-benzodioxane, 1,3-benzodioxole, 1-benzopyr-2-en-4-one, indole, isatin, 1,3-quinazolin-4-one, and quinoline.
 12. A compound according to claim 11 wherein R₃ is a “trans-cinnamide”; and Ar is selected from 1,3-benzimidazol-2-one, 1,4-benzodioxane, 1,3-benzodioxole, 1-benzopyr-2-en-4-one, indole, isatin, phenyl, 1,3-quinazolin-4-one, and quinoline .
 13. A compound according to claim 12 wherein one or both of R₁₀ and R₁₁ are each independently selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, hydroxyalkyl, and heterocyclylalkyl.
 14. A compound according to claim 12 wherein NR₁₀R₁₁ is R₁₀ and R ₁₁ are taken together with N to form an unsubstituted heterocyclyl group or a substituted heterocyclyl as described above group.
 15. A composition comprising a compound of according to claim 1 in and a pharmaceutically-acceptable carrier.
 16. A method of inhibiting inflammation comprising the administration of a compound of claim 1 formula I to a patient:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R₁ , R ₂ , R ₃ , R ₄ , and R ₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, with the proviso that at least one of R₁ and R ₃ is a “cis-cinnamide” or a “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R₁₀ and R ₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or R₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4) cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8) heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11) hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14) carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17) aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20) carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23) alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26) alkylsulfonyl, and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents, are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide”.
 17. A method of inhibiting inflammation comprising the administration of a composition comprising a compound of claim 15 formula I to a patient:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R₁ , R ₂ , R ₃ , R ₄ , and R ₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, with the proviso that at least one of R₁ and R ₃ is a “cis-cinnamide” or a “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R₁₀ and R ₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or R₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4) cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8) heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11) hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14) carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17) aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20) carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23) alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26) alkylsulfonyl, and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents, are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide” and a pharmaceutically-acceptable carrier.
 18. A method of suppressing immune response comprising the administration of a compound of claim 1 formula I to a patient:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, with the proviso that at least one of R ₁ and R ₃ is a “cis-cinnamide” or a “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R ₁₀ and R ₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or R ₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1 ) alkyl, 2 ) alkoxy, 3 ) alkoxyalkyl, 4 ) cycloalkyl, 5 ) aryl, 6 ) heterocyclyl, 7 ) heterocyclylcarbonyl, 8 ) heterocyclylalkylaminocarbonyl, 9 ) hydroxy, 10 ) hydroxyalkyl, 11 ) hydroxyalkoxyalkyl, 12 ) carboxy, 13 ) carboxycarbonyl, 14 ) carboxaldehyde, 15 ) alkoxycarbonyl, 16 ) arylalkoxycarbonyl, 17 ) aminoalkanoyl, 18 ) carboxamido, 19 ) alkoxycarbonylalkyl, 20 ) carboxamidoalkyl, 21 ) alkanoyl, 22 ) hydroxyalkanoyl, 23 ) alkanoyloxy, 24 ) alkanoylamino, 25 ) alkanoyloxyalkyl, and 26 ) alkylsulfonyl, and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents, are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide”.
 19. A method of suppressing immune response comprising the administration of a composition comprising a compound of claim 15 formula I to a patient:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R₁ , R ₂ , R ₃ , R ₄ , and R ₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, with the proviso that at least one of R₁ and R ₃ is a “cis-cinnamide” or a “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R ₁₀ and R ₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or R ₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1 ) alkyl, 2 ) alkoxy, 3 ) alkoxyalkyl, 4 ) cycloalkyl, 5 ) aryl, 6 ) heterocyclyl, 7 ) heterocyclylcarbonyl, 8 ) heterocyclylalkylaminocarbonyl, 9 ) hydroxy, 10 ) hydroxyalkyl, 11 ) hydroxyalkoxyalkyl, 12 ) carboxy, 13 ) carboxycarbonyl, 14 ) carboxaldehyde, 15 ) alkoxycarbonyl, 16 ) arylalkoxycarbonyl, 17 ) aminoalkanoyl, 18 ) carboxamido, 19 ) alkoxycarbonylalkyl, 20 ) carboxamidoalkyl, 21 ) alkanoyl, 22 ) hydroxyalkanoyl, 23 ) alkanoyloxy, 24 ) alkanoylamino, 25 ) alkanoyloxyalkyl, and 26 ) alkylsulfonyl, and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents, are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide” and a pharmaceutically-acceptable carrier.
 20. A compound according to claim 1 selected from: ( 2,4-Dichlorophenyl)[2 -(E-(( 6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2 -(E-(( 3 -( 1 -imidazolyl)propylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 2-hydroxyethylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-((bis-( 2-hydroxyethyl)ainino)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 3 -( 2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 4-methylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 4 -( 2-pyridyl)piperazin-1 -yl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -(Hydroxymethyl)phenyl) ( 2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -Bromophenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 4 -( 2-hydroxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 4 -( 2-hydroxyethoxyethyl)piperazin-1 -yl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -Bromophenyl)[2-chloro-4 -(E-(( 3 -(hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -Bromophenyl)[2-chloro-4 -(E-(( 2 -(hydroxymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -Bromophenyl)[2-chloro-4 -(E-(( 3-acetamidopyrrolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -Bromophenyl)[2-chloro-4 -(E-(( 4 -(hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -Bromophenyl)[2-chloro-4 -(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 3-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-chloro-4 -(E-(( 4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Bromophenyl)[2-chloro-4 -(E-(( 4-acetylhomopiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -Bromophenyl)[2-chloro-4 -(E-((thiomorpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Bromophenyl)[2-chloro-4 -(E-(( 4 -( 2-oxo,-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Bromophenyl)[2-chloro-4 -(E-(( 2-tetrahydroisoquinolinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Methylphenyl)[2-trifluoromethyl-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Methylphenyl)[2-trifluoromethyl-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Methylphenyl)[2-trifluoromethyl-4 -(E-(( 2 -( 1-morpholinyl)ethylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2-Methylphenyl)[2-trifluoromethyl-4 -(E-(( 4-phenylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Methylphenyl)[2-trifluoromethyl-4 -(E-(( 3 -( 2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2-Methylphenyl)[2-trifluoromethyl-4 -(E-((cyclopropylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl) 2-nitro-4 -(E-(( 3 -( 2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2,3-Dichlorophenyl)[2 -nitro-4-(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 4-Bromophenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 4-Methylphenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-nitro-4 -(E-(( 4 -(tert-butoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-nitro-4 -(E-(( 4 -( 2-furoylcarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-nitro-4 -(E-(( 4 -(methanesulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-nitro-4 -(E-(( 4 -(diethylaminocarbonylmethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-nitro-4 -(E-(( 4 -(diethylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl) ( 2-nitro-4 -(E-(( 4 -(carboxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-nitro-4 -(E-(( 4 -(carboxymethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Methylphenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Chlorophenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Aminophenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Hydroxymethylphenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Ethylphenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-iso-Propylphenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-tert-Butylphenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Chlorophenyl)[2-chloro-4 -(E-(( 4-acetylpiperain-1-yl)carbonyl)) 2-propenyl)phenyl]sulfide; ( 2 -( 1-Morpholinylmethyl)phenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -( 4 -( 1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -( 4 -(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Formylphenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -( 4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2 -(E-(( 1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Formylphenyl)[2-nitro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; ( 2-Formylphenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide, N,N-dimethyl hydrazone; ( 2 -(( 3 -( 1-Morpholinyl)propyl)- 1-amino)phenyl)[2-chloro-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-bromo-4 -(E-(( 3 -( 2-oxopyrrolidin-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide; ( 2,4-Dichlorophenyl)[2-formyl-4 -(E-(( 1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide; and ( 2-Chloro-6-formylphenyl)[2-chloro-4 -(E-(( 4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide.
 21. A compound of formula I:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, with the proviso that at least one of R ₁ and R ₃ is a “cis-cinnamide” or a “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R ₁₀ and R ₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or R ₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1 ) alkyl, 2 ) alkoxy, 3 ) alkoxyalkyl, 4 ) cycloalkyl, 5 ) aryl, 6 ) heterocyclyl, 7 ) heterocyclylcarbonyl, 8 ) heterocyclylalkylaminocarbonyl, 9 ) hydroxy, 10 ) hydroxyalkyl, 11 ) hydroxyalkoxyalkyl, 12 ) carboxy, 13 ) carboxycarbonyl, 14 ) carboxaldehyde, 15 ) alkoxycarbonyl, 16 ) arylalkoxycarbonyl, 17 ) aminoalkanoyl, 18 ) carboxamido, 19 ) alkoxycarbonylalkyl, 20 ) carboxamidoalkyl, 21 ) alkanoyl, 22 ) hydroxyalkanoyl, 23 ) alkanoyloxy, 24 ) alkanoylamino, 25 ) alkanoyloxyalkyl, and 26 ) alkylsulfonyl, and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide”, subject to the proviso that when R ₃ is a “cis-cinnamide” or a “trans-cinnamide,” as defined above, one or more than one of the following conditions is fulfilled: (A) R ₁ , as defined above, is other than hydrogen; (B) R ₈ and R ₉ are both hydrogen and Ar is not pyridyl; and (C) R ₁₀ and R ₁₁ are taken together with N to form a substituted or unsubstituted heterocyclyl group, as defined above.
 22. A compound of formula I:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, with the proviso that at least one of R ₁ and R ₃ is a “cis-cinnamide” or a “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R ₁₀ and R ₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or R ₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1 ) alkyl, 2 ) alkoxy, 3 ) alkoxyalkyl, 4 ) cycloalkyl, 5 ) aryl, 6 ) heterocyclyl, 7 ) heterocyclylcarbonyl, 8 ) heterocyclylalkylaminocarbonyl, 9 ) hydroxy, 10 ) hydroxyalkyl, 11 ) hydroxyalkoxyalkyl, 12 ) carboxy, 13 ) carboxycarbonyl, 14 ) carboxaldehyde, 15 ) alkoxycarbonyl, 16 ) arylalkoxycarbonyl, 17 ) aminoalkanoyl, 18 ) carboxamido, 19 ) alkoxycarbonylalkyl, 20 ) carboxamidoalkyl, 21 ) alkanoyl, 22 ) hydroxyalkanoyl, 23 ) alkanoyloxy, 24 ) alkanoylamino, 25 ) alkanoyloxyalkyl, and 26 ) alkylsulfonyl, and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide”, subject to the proviso that one or more than one of the following conditions is fulfilled: (A) Ar is an unsubstituted heteroaryl group, a substituted heteroaryl group, or a substituted aryl group; (B) two or more than two of R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ , as defined above, are other than hydrogen; and (C) R ₁₀ and R ₁₁ are taken together with N to form a substituted or unsubstituted heterocyclyl group, as defined above.
 23. A compound of formula I:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R ₁ , R ₂ , R ₄ , and R ₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, where R ₃ is a “cis-cinnamide” or “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R ₁₀ and R ₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or R ₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1 ) alkyl, 2 ) alkoxy, 3 ) alkoxyalkyl, 4 ) cycloalkyl, 5 ) aryl, 6 ) heterocyclyl, 7 ) heterocyclylcarbonyl, 8 ) heterocyclylalkylaminocarbonyl, 9 ) hydroxy, 10 ) hydroxyalkyl, 11 ) hydroxyalkoxyalkyl, 12 ) carboxy, 13 ) carboxycarbonyl, 14 ) carboxaldehyde, 15 ) alkoxycarbonyl, 16 ) arylalkoxycarbonyl, 17 ) aminoalkanoyl, 18 ) carboxamido, 19 ) alkoxycarbonylalkyl, 20 ) carboxamidoalkyl, 21 ) alkanoyl, 22 ) hydroxyalkanoyl, 23 ) alkanoyloxy, 24 ) alkanoylamino, 25 ) alkanoyloxyalkyl, and 26 ) alkylsulfonyl, and Ar is an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide”, wherein when Ar is pyridyl, Ar is substituted by two or more than two substituents.
 24. A compound according to claim 23 where one or more than one of R₁ , R ₂ , R ₄ , and R ₅ are other than hydrogen.
 25. A compound according to claim 23 where R₁₀ and R ₁₁ are taken together with N to form a substituted or unsubstituted heterocyclyl group.
 26. A compound of formula I:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R ₁ , R ₂ , R ₄ , and R ₅ are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, subject to the proviso that one or more than one of R ₁ , R ₂ , R ₄ , and R ₅ are other than hydrogen, where R ₃ is a “cis-cinnamide” or “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R ₁₀ and R ₁₁ are each independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl, or R ₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1 ) alkyl, 2 ) alkoxy, 3 ) alkoxyalkyl, 4 ) cycloalkyl, 5 ) aryl, 6 ) heterocyclyl, 7 ) heterocyclylcarbonyl, 8 ) heterocyclylalkylaminocarbonyl, 9 ) hydroxy, 10 ) hydroxyalkyl, 11 ) hydroxyalkoxyalkyl, 12 ) carboxy, 13 ) carboxycarbonyl, 14 ) carboxaldehyde, 15 ) alkoxycarbonyl, 16 ) arylalkoxycarbonyl, 17 ) aminoalkanoyl, 18 ) carboxamido, 19 ) alkoxycarbonylalkyl, 20 ) carboxamidoalkyl, 21 ) alkanoyl, 22 ) hydroxyalkanoyl, 23 ) alkanoyloxy, 24 ) alkanoylamino, 25 ) alkanoyloxyalkyl, and 26 ) alkylsulfonyl, and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide”.
 27. A compound according to claim 26 where R₁₀ and R ₁₁ are taken together with N to form a substituted heterocyclyl group or an unsubstituted heterocyclyl group.
 28. A compound of formula I:

or a pharmaceutically-acceptable salt or pharmaceutically-acceptable prodrug of a compound of formula I, wherein R ₁ , R ₂ , R ₄ , and R ₅ are each independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, and h. carboxaldehyde, where R ₃ is a “cis-cinnamide” or “trans-cinnamide”, defined as

where R₈ and R ₉ are each independently selected from a. hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl, and e. dialkylaminocarbonylalkyl, R ₁₀ and R ₁₁ are taken together with the N to form an unsubstituted heterocyclyl group, or a substituted heterocyclyl group, where the substituted heterocyclyl group is substituted by one or more than one substituent, where the substituents are each independently selected from 1 ) alkyl, 2 ) alkoxy, 3 ) alkoxyalkyl, 4 ) cycloalkyl, 5 ) aryl, 6 ) heterocyclyl, 7 ) heterocyclylcarbonyl, 8 ) heterocyclylalkylaminocarbonyl, 9 ) hydroxy, 10 ) hydroxyalkyl, 11 ) hydroxyalkoxyalkyl, 12 ) carboxy, 13 ) carboxycarbonyl, 14 ) carboxaldehyde, 15 ) alkoxycarbonyl, 16 ) arylalkoxycarbonyl, 17 ) aminoalkanoyl, 18 ) carboxamido, 19 ) alkoxycarbonylalkyl, 20 ) carboxamidoalkyl, 21 ) alkanoyl, 22 ) hydroxyalkanoyl, 23 ) alkanoyloxy, 24 ) alkanoylamino, 25 ) alkanoyloxyalkyl, and 26 ) alkylsulfonyl, and Ar is an unsubstituted aryl group, an unsubstituted heteroaryl group, a substituted aryl group, or a substituted heteroaryl group, where the substituted aryl group and the substituted heteroaryl group are substituted by one or more than one substituent, where the substituents are each independently selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k. alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted heterocyclylalkyl, m. substituted heterocyclylalkyl, n. carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q. alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s. cyano, t. amino, u. heterocyclylalkylamino, and v. “trans-cinnamide”.
 29. A compound according to claim 1 wherein Ar is an unsubstituted heteroaryl group or a substituted heteroaryl group and wherein the heteroaryl group is selected from benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:

wherein X* and Z* are independently selected from —CH₂ —, —CH ₂ NH—, —CH ₂ O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH ₂ —, and Y* is selected from —C(O)— and —(C(R″)₂)_(v) — where R′ is hydrogen or C ₁₋₄ alkyl and v is 1-3.
 30. A compound according to claim 21, wherein Ar is an unsubstituted heteroaryl group or a substituted heteroaryl group and wherein the heteroaryl group is selected from benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:

wherein X* and Z* are independently selected from —CH₂ —, —CH ₂ NH—, —CH ₂ O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH ₂ —, and Y* is selected from —C(O)— and —(C(R″)₂)_(v) — where R′ is hydrogen or C ₁₋₄ alkyl and v is 1-3.
 31. A compound according to claim 22 wherein Ar is an unsubstituted heteroaryl group or a substituted heteroaryl group and wherein the heteroaryl group is selected from benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:

wherein X* and Z* are independently selected from —CH₂ —, —CH ₂ NH—, —CH ₂ O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH ₂ —, and Y* is selected from —C(O)— and —(C(R″)₂)_(v) — where R′ is hydrogen or C ₁₋₄ alkyl and v is 1-3.
 32. A compound according to claim 23 wherein Ar is an unsubstituted heteroaryl group or a substituted heteroaryl group and wherein the heteroaryl group is selected from benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:

wherein X* and Z* are independently selected from —CH₂ —, —CH ₂ NH—, —CH ₂ O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH ₂ —, and Y* is selected from —C(O)— and —(C(R″)₂)_(v) — where R′ is hydrogen or C ₁₋₄ alkyl and v is 1-3.
 33. A compound according to claim 26 wherein Ar is an unsubstituted heteroaryl group or a substituted heteroaryl group and wherein the heteroaryl group is selected from benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:

wherein X* and Z* are independently selected from —CH₂ —, —CH ₂ NH—, —CH ₂ O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH ₂ —, and Y* is selected from —C(O)— and —(C(R″)₂)_(v) — where R′ is hydrogen or C ₁₋₄ alkyl and v is 1-3.
 34. A compound according to claim 27 wherein Ar is an unsubstituted heteroaryl group or a substituted heteroaryl group and wherein the heteroaryl group is selected from benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:

wherein X* and Z* are independently selected from —CH₂ —, —CH ₂ NH—, —CH ₂ O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH ₂ —, and Y* is selected from —C(O)— and —(C(R″)₂)_(v) — where R′ is hydrogen or C ₁₋₄ alkyl and v is 1-3.
 35. A compound according to claim 28 wherein Ar is an unsubstituted heteroaryl group or a substituted heteroaryl group and wherein the heteroaryl group is selected from benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:

wherein X* and Z* are independently selected from —CH₂ —, —CH ₂ NH—, —CH ₂ O—, —NH—, and —O— with the proviso that at least one of X* and Z* is not —CH ₂ —, and Y* is selected from —C(O)— and —(C(R″)₂)_(v) — where R′ is hydrogen or C ₁₋₄ alkyl and v is 1-3. 